Clinical trial NCT03687125
Conditions: Multiple Myeloma in Relapse Multiple Myeloma Progression Multiple Myeloma With Failed Remission
Sponsor: Mundipharma-EDO GmbH
Start date: 2018-10-15; Completion date: 2019-04-17
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Phase 1

The primary objectives of Phase 1 of this study are to:

* Establish the safety, toxicity, and maximum tolerated dose (MTD) of the tinostamustine conditioning regimen.
* Identify the recommended Phase 2 dose (RP2D) of tinostamustine for use in the Phase 2 portion of the study.

The secondary objective of Phase 1 of this study is to:

\- Investigate the pharmacokinetics (PK) of tinostamustine.

Detailed description:
Study Design (Methodology):

This is a 2-part, international, multi-center, open-label study of salvage treatment with tinostamustine conditioning followed by ASCT in participants with relapsed/ refractory multiple myeloma (MM). (ASCT is defined as salvage if the participant had already received a prior ASCT and undergoes a second ASCT after evidence of progressive disease \[PD\].) Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of defining the dose limiting toxicities (DLTs) of the tinostamustine conditioning regimen and defining the MTD and RP2D for use in the Phase 2 portion of the study.

The Safety Review Committee can make a decision to stop dose escalation or explore intermediary doses at any time. The total dose of tinostamustine will be administered on Day -1. Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up to 31 participants initially will be enrolled. If lesser than or equal to (\<=) 25 participants of these initial 31 participants experience a response, then no additional participants will be enrolled. However, if greater than (\>) 25 participants in Stage 1 of Phase 2 experience a response, then enrollment in this cohort will continue, with up to 71 participants enrolled. In Phase 2 of the study, all participants will receive tinostamustine at the RP2D administered in Phase 1 according to the same schedule. After provision of written informed consent, participants will be screened for study eligibility within 28 days before Day 1 (the day of ASCT). Participants who have a minimum of 2×106 CD34+ cells/kg cryopreserved and are otherwise determined to be eligible, based on screening assessments, will be enrolled and receive the tinostamustine conditioning regimen. The tinostamustine dose will be administered 24 hours pre-ASCT (i.e., Day -1). On Day 1, ASCs will be administered intravenously (IV) according to standard institutional practice. Participants will receive supportive measures (including growth factor support post-ASCT, antimicrobial prophylaxis, red blood cell and platelet transfusion, and treatment for neutropenic fever) according to standard institutional practice.

Arms: arm 1: Participants received single dose of tinostamustine 180 milligrams per meter square (mg/m\^2) intravenous (IV) injection on Day -1 followed by autologous stem cell transplantation (ASCT) on Day 1. arm 2: Participants received single dose of tinostamustine 220 mg/m\^2 IV injection on Day -1 followed by ASCT on Day 1.
Interventions: intervention 1: Tinostamustine intervention 2: Autologous Stem Cell Transplant (ASCT)
Intervention descriptions: intervention 1: Participants received tinostamustine IV injection. intervention 2: Undergo autologous stem cell transplant

Protocol documents:
Prot_000.pdf: 
16.1 Study Information 
16.1.1 
Protocol and protocol amendments 
v Protocols 
P Original Protocol V1.0 20 Mar 2018  
P Protocol  V2.0 18 Jun 2018 
v Protocol Clarification Memos: 
P 21 Sep 2018 
P 25 Oct 2018 
P 17 Dec 2018 
P 30 Jan 2019 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
1
CCI


Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
2
PPD
PPD
PPD
PPD
CCI


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
2 
Version 1.0 (Original) 
INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by Mundipharma EDO, or its 
designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Ethics Committee (EC). No changes will be made to the 
study protocol without the prior written approval of Mundipharma EDO and the IRB/EC, 
except where necessary to eliminate an immediate hazard to a patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
Investigator Signature 
Date 
 
Printed Name 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
3


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
4
PPD
PPD
PPD
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Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
4 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
• 
Investigate the pharmacokinetics (PK) of tinostamustine. 
Phase 2 
The primary objectives of Phase 2 of the study are to: 
• 
Investigate the efficacy of the tinostamustine conditioning regimen at the RP2D dose. 
• 
Investigate the safety of the tinostamustine conditioning regimen. 
The secondary objective of Phase 2 of this study is to: 
• 
Evaluate the PK of tinostamustine. 
Endpoints 
Efficacy 
The primary efficacy endpoint in Phase 2 of the study is: 
• 
Objective response rate (ORR): complete response [CR], very good partial response [VGPR] and 
partial response [PR]  at Day 100 (±7 days) post-autologous stem cell transplant (ASCT). 
Secondary efficacy endpoints among patients treated at the RP2D (in Phases 1 and 2) are: 
• 
ORR, and, in patients who achieve CR, minimal residual disease-negativity (MRD-N), as 
determined by next-generation flow cytometry at Day 100 (±7 days) post-ASCT. 
Safety 
The safety endpoint in Phase 1 of the study is: 
• 
Dose-limiting toxicities (DLT). 
Additional safety endpoints in Phases 1 and 2 of the study are: 
• 
Incidence of neutrophil and platelet engraftment failure. 
• 
Duration of cytopenia (i.e., absolute neutrophil count [ANC] ≤0.5×109/L, platelet count 
≤20×109/L). 
• 
Cumulative incidence of treatment-related mortality (TRM). 
• 
Transplant-related non-hematologic Grade 3 toxicity over time through Day 30, stratified by 
hematopoietic cell transplantation comorbidity index (HCT-CI).  
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
5


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
5 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
• 
Incidence of adverse events (AEs) and serious adverse events (SAEs). 
• 
Change from baseline in standard safety hematology and clinical chemistry test results. 
Study Design (Methodology):  
This is a 2-part, international, multi-center, open-label study of salvage treatment with tinostamustine 
conditioning followed by ASCT in patients with relapsed/ refractory multiple myeloma (MM). (ASCT is 
defined as salvage if the patient had already received a prior ASCT and undergoes a second ASCT after 
evidence of progressive disease [PD].)  
Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of defining the 
DLTs of the tinostamustine conditioning regimen and defining the MTD and RP2D for use in the Phase 2 
portion of the study.  
The initial dose of tinostamustine in the Phase 1 portion of the study is 180 mg/m2, with escalation to 220, 
260, and then 300 mg/m2 (or higher) planned. If the 180 mg/m2 dose level is not tolerable, then a lower 
tinostamustine dose of 160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, with 
<33% of patients experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may be explored. 
The Safety Review Committee can make a decision to stop dose escalation or explore intermediary doses 
at any time. 
The total dose of tinostamustine will be administered on Day -1.  
Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up to 
31 patients initially will be enrolled. If ≤25 patients of these initial 31 patients experience a response, then 
no additional patients will be enrolled. However, if >25 patients in Stage 1 of Phase 2 experience a 
response, then enrollment in this cohort will continue, with up to 71 patients enrolled. In Phase 2 of the 
study, all patients will receive tinostamustine at the RP2D administered in Phase 1 according to the same 
schedule. 
After provision of written informed consent, patients will be screened for study eligibility within 28 days 
before Day 0 (the day of ASCT). Patients who have a minimum of 2×106 CD34+ cells/kg cryopreserved 
and are otherwise determined to be eligible, based on screening assessments, will be enrolled and receive 
the tinostamustine conditioning regimen. The tinostamustine dose will be administered 24 hours pre-
ASCT (i.e., Day -1). 
On Day 1, ASCs will be administered intravenously (IV) according to standard institutional practice.  
Patients will receive supportive measures (including growth factor support post-ASCT, antimicrobial 
prophylaxis, red blood cell and platelet transfusion, and treatment for neutropenic fever) according to 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
6


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
6 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
standard institutional practice. 
During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 Day 30 (±5 
days) post-ASCT or until all transplant-related toxicity resolves. Patients will be discharged from the 
study center once the following engraftment criteria are met: 
• 
Neutrophil engraftment is defined as the first of 3 consecutive days with ANC >0.5×109/L.  
• 
Platelet engraftment will be defined as the first of 3 consecutive days of platelet count >20×109/L 
without platelet transfusion in the prior 7 days. 
Thereafter, patients will attend study center visits at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
Definition of DLT 
Toxicity will be assessed by the Investigator using the US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
In Phase 1 of the study, DLT is defined as the occurrence of any of the following events occurring within 
30 days post-ASCT that are considered by the Investigator to be at least possibly related to 
tinostamustine: 
• 
Delayed engraftment (>30 days after ASCT). Engraftment will be considered delayed if the 
subject has not met criteria for both neutrophil and platelet engraftment:  
- Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
- Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days.  
• 
QTcF >500 msec or >60 msec increase from baseline, with a duration of >30 minutes, or 
≥Grade 3 QTcF interval prolongation accompanied by ventricular arrhythmia. Baseline QTcF 
interval will be the mean value determined during triplicate ECG(s) at Day -1 (-1day), before 
study drug administration; the mean QTcF will be confirmed by the cental laboratory.  
• 
Grade 4 non-hematologic toxicity  
• 
Grade 3, non-hematologic toxicity related to treatment, with the exception of: 
- Nausea or vomiting  
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
7


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
7 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
- Diarrhea  
- Fatigue, dehydration, or glucose intolerance 
- Skin rash, dry skin, or pruritus responsive to topical or systemic steroids 
- Fever (>40ºC for ≤24 hours) 
- Infection 
- Dyspnea, hypoxia, or pneumonitis 
- Abdominal pain 
- Dysphagia, oral mucositis, oral pain, or anorexia 
- Flu-like syndrome 
- Engraftment syndrome  
- Weight loss 
- Pain, pain in extremity, headache, or insomnia 
- Hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, or hypophosphatemia 
- Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, 
or alkaline phosphatase 
- Alopecia 
Dose Escalation Scheme 
In Phase 1, up to 3 patients initially are to be enrolled in each cohort. The first patient enrolled in the 
initial cohort must complete the study through engraftment without a ≥Grade 3 toxicity or through 
30 days post-ASCT without a DLT, whichever occurs first, before additional patients may be enrolled in 
that initial cohort. (If the first patient experiences a DLT, then a lower dose will be explored for the 
second patient, and so on.) 
• 
If the first patient does not experience a DLT or experiences engraftment without a ≥Grade 3 
toxicity, the next 2 patients may be enrolled simultaneously. 
After 3 patients in a cohort complete the study through engraftment without a ≥Grade 3 toxicity or 
through 30 days post-ASCT without a DLT, whichever occurs first, and have safety evaluations 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
8


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
8 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
performed through that time, and: 
• 
None of these 3 patients experience a DLT, then enrollment of the next cohort may commence 
with approval from the Safety Committee. 
• 
1 of 3 patients within a cohort experiences a DLT, then up to 3 additional patients are to be 
enrolled sequentially at that dose level. If none of the additional 3 patients has a DLT (i.e., 1 of 
6 patients has a DLT), then enrollment at the next scheduled dose may commence with approval 
from the Safety Committee. 
• 
If ≥2 patients within a cohort experience a DLT, then the DLT dose level will have been reached 
and the previous lower dose level will be considered the MTD. (If ≥2 patients in the initial dose 
cohort experience DLTs, then the dose will be reduced to one level lower and the same procedure 
will be followed.) 
A total of 6 patients are planned to be treated at the MTD to confirm the RP2D before enrollment of 
patients in Phase 2 of the study. If the MTD is not confirmed at this stage, the dose will be reduced to one 
level lower and the same procedure will be followed. 
Note that enrollment in the next dose cohort can begin only when the last patient enrolled in the current 
dose cohort completes the study through engraftment without a ≥Grade 3 toxicity or through 30 days 
post-ASCT without a DLT, whichever occurs first, provided that <2 patients in the current dose cohort 
experienced a DLT.  
Although decisions regarding dose escalation will be made based on review of data through Day 30 post-
ASCT, safety data will also be collected from all patients continuing in the study and this will be 
reviewed periodically by the Safety Committee. Any detected toxicity may necessitate further refinement 
of the RP2D. 
Definition of MTD: 
The MTD is defined as the highest dose level at which ≤1 of 6 patients experiences DLT through 30 days 
post-ASCT. 
Definition of RP2D: 
The RP2D may be equal to or higher than the preliminary MTD, but less than the non-tolerated dose (i.e., 
the dose at which ≥2 of 6 patients experienced DLT). The RP2D will be determined in discussion with the 
Sponsor, Medical Monitor, and Investigators.  
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
9


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
9 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
Number of Subjects:  
Phase 1 
A total of 9-12 patients are planned to be enrolled in Phase 1.  
Phase 2 
A total of up to 71 patients are planned to be enrolled in Phase 2.  
Criteria for Inclusion/Exclusion: 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for enrollment: 
1. Patient has MM and: 
a. Has received prior ASCT after standard first-line induction treatment. 
b. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18 months in 
Phase 2. 
Progression Free Inteval is defined as the time from date of ASCT to PD. 
c. Received treatment with ≤3 prior lines of therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. When 
patients have undergone sequential phases of treatment without intervening progression, such 
as induction, collection of peripheral blood stem cells, transplantation and 
consolidation/maintenance, this is considered to be 1 line of treatment. A new line of therapy 
is initiated as a result of PD or relapse (Garderet et al, 2017). 
2. CR, VGPR, PR, or minimal response (MR) to latest of salvage chemotherapy at relaps, as 
determined by the International Myeloma Working Group (IMWG) criteria.  
3. Is, in the Investigator’s opinion, a candidate for consolidation therapy with tinostamustine 
followed by ASCT. (Note that patients planned to receive tandem ASCT are not eligible for the 
Phase 1 portion of the study.) 
4. Has available autologous peripheral blood stem cell (PBSC) product with CD34 cell dose ≥2×106 
cells/kg. The product could be from a collection prior to first ASCT or later second collection. 
(Note that, although not required, in Phase 1, the Investigator should consider enrolling patient 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
10


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
10 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
with a large number of available PBSCs to permit subsequent ASCT, as patients in Stage 1 may 
received a dose lower that that determined to be effective.) 
5. Age 18-75 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score <3 at Screening. 
7. Creatinine clearance ≥40 mL/min, as determined by a local laboratory using the Cockcroft-Gault 
equation within 28 days before ASCT. 
8. Left ventricular ejection fraction (LVEF) ≥40% within 28 days before ASCT. 
9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), forced 
vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) >50% predicted within 28 
days before ASCT.  
10. Adequate liver function, as defined by an ALT and AST ≤2.5 × the upper limit of normal (ULN) 
and bilirubin ≤1.5 × ULN within 28 days before ASCT.  
11. Potassium within the local laboratory’s normal range. (Potassium supplementation is 
permissible.) 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment in the study: 
1. History of central nervous system (CNS) disease involvement. 
2. Myocardial infarction (MI) or stroke within 6 months before Screening.  
3. Uncontrolled acute infection. 
4. HCT-CI >6 points. 
5. Concurrent malignant disease with the exception of treated basalioma/spinalioma of the skin or 
early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment for other 
malignancies (not listed above) must have been terminated at least 24 months before registration 
and no evidence of active disease shall be documented since then. 
6. Major coagulopathy or bleeding disorder. 
7. Other serious medical condition that could potentially interfere with the completion of treatment 
according to this protocol or that would impair tolerance to therapy or prolong hematological 
recovery. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
11


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
12
CCI
CCI


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
12 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
Patients may receive the following supportive care:   
• 
IV hydration and anti-emetics, in accordance with institutional guidelines. 
• 
Growth factor support with pegfilgrastim or equivalent agent post-ASCT, in accordance with 
institutional guidelines.  
• 
Standard supportive care, in accordance with institutional guidelines, including blood product 
transfusions, antimicrobial prophylaxis, and treatment for febrile neutropenia. 
Duration of Treatment and Study Duration:  
All patients will receive 1 doses of tinostamustine on Days -1 followed by ASCT on Day 1. 
The anticipated accrual is 9-12 patients/year in Phase 1. Recruitment will continue during the evaluation 
period needed for Stage 1 of Phase 2. All patients will be followed for a maximum of 130 (±7 days) post-
ASCT thus yielding a study of total duration of approximately 2.5 to 3.5 years.  
Criteria for Evaluation: 
Efficacy Assessment(s):  
Response will be determined by the Investigator using the IMWG criteria. In addition, response of each 
subject will be evaluated by two independent reviewers, otherwise not involved in the clinical trial.  In 
order to assess response, M protein component is to be measured in serum and/or urine, free light chain 
(FLC) testing is to be performed. Note that in the case of immunoglobulin A (IgA) MM, MM IgA values 
should be used. Bone marrow aspirate or biopsy and imaging studies (e.g., computed tomography, 
magnetic resonance imaging) are to be performed as clinically indicated. For patients with CR, based on 
serum and urine analysis, bone marrow aspirate and biopsies are to be performed at Day 100 (±7days), 
including the myeloma immunophenotype.  
Confirmatory assessment: A second assessment of response will be conducted within Day 130 (±7days), 
the latest, to confirm the response. If the result is not confirmed by a second evaluation, the status is either 
Non Evaluable (NE) or the prior disease status remains valid. Confirmation should be obtained for 
biochemical markers but ius not necessary for bone marrow or imaging studies, 
Assessment of M protein in serum and urine should be performed any time relapse is suspected. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
13


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
14
CCI


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
14 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
All patients in the safety set with at least one quantifiable pre-dose and one quantifiable post-dose PK 
plasma concentration will be included in the PK set.  
Dependent of the specific analysis, these sets will be taken from the cohort for Phase 1, for Phase 2 
(RP2D), or both phases pooled. 
Efficacy Analyses:   
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Summaries for categorical variables 
will include frequency counts and percentages. 
Superiority testing will be performed on FAS in Phase 2 cohort to investigate the null hypothesis that the 
primary endpoint of responder rate is below or equal to the gold standard against the alternative 
hypothesis that it is higher than the gold standard. The gold standard is assumed to be 77.5% (CIBMTR 
report, December 2017) and a 1-sided, 2-step chi-square test will be performed at the 2.5% level of 
significance for FAS.  
For the primary endpoint, also an upper 1-sided 97.5% confidence interval will be calculated for FAS in 
addition to summary statistics. 
For the primary endpoint in other sets and for the secondary endpoints of other responder rates in the 
FAS, also 2-sided 95% confidence intervals will be calculated in addition to summary statistics. 
Interim Analyses: 
In Phase 2 of the study, at the completion of the Stage 1 with 31 patients, an interim analysis will be 
performed using the FAS for the Phase 2 cohort to determine whether enrollment will continue in Stage 2. 
If >25 of 31 patients in Stage 1 experience a response to treatment, then enrollment will continue into 
Stage 2, with up to 40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a 
response to treatment, no further patients will be enrolled (in the ongoing Stage 2 recruitment).   
Pharmacokinetic Analyses:  
PK analysis for tinostamustine and its metabolites will be performed using the PK set.  
PK parameters at all doses will include maximum plasma concentration (Cmax), time to maximum plasma 
concentration (tmax), half-life (t½) area under the plasma concentration curve from 0 to 12 hours 
(AUC0-12), area under the plasma concentration curve from time 0 to time t (AUC0-t), apparent total 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
15


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
15 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
clearance (CL/F), apparent volume of distribution (Vd/F), and terminal disposition rate constant (λz). The 
initial calculation of PK parameters will be performed using non-compartmental analysis. Plasma 
concentrations and PK parameters will be summarized by dose. 
Summaries will include the number of observations (n), arithmetic or geometric mean, SD or coefficient 
of variation (CoV), median, minimum, and maximum. 
Safety Analyses: 
Safety data, including changes from baseline if applicable will be summarized at each dose level for the 
safety set. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Summaries for categorical variables will include frequency 
counts and percentages. 
Sample Size Rationale 
Across both Phases 1 and 2 of the study, a total of up to ~86 patients may be enrolled. 
For Phase 1, a formal sample size determination/power calculation was not performed. Based on 
experience from previously published similar studies, a total number of 9 (minimum) to 15 (maximum) 
patients in the dose escalation stage of the study are foreseen. 
For Phase 2 of the study, superiority testing will be performed to investigate the null hypothesis that the 
primary endpoint of responder rate is below or equal to the gold standard against the alternative 
hypothesis that it is higher than the gold standard. The gold standard is assumed to be 77.5% (CIBMTR 
report, December 2017) and a one-sided chi-square test will be performed at the 2.5% level of 
significance. For power considerations, the alternative working hypothesis is that the responder rate for 
the study drug is at least 90%. 
In the methodology proposed by Simon (Simon, 1989), a Phase 2 design can be represented by 
4 numbers: N1, R1, N, and R. N1 is the sample size in the first stage. R1 is the critical value in the first 
stage. If R1 or fewer responses occur in the N1 patients, the study treatment is rejected. N is the combined 
sample size for both the first and second stages. R is the critical value in the combined sample. If R or 
fewer of the N patients respond, the study treatment is rejected at the end. 
The design is found with PASS Sample Size Software through an exhaustive search of all possible 
designs (combinations of R1, N1, R and N) that control alpha (0.025) and beta (0.20, meaning power is 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
16


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
16 
Version 1.0 (Original) 
Name of Sponsor  
Mundipharma-EDO GmbH 
 
 
Name of Finished Product: 
Tinostamustine hydrochloride (Formerly EDO-S101) 
Name of Active Ingredient: 
Tinostamustine hydrochloride 
Protocol No.:   
EDO-S101-1004 
Temporary (T) No.: 
 
<EUDRACT><IND> No.:  
 
0.80). With the minimax approach, the design is selected that has the lowest N. 
Per the minimax design, 31 patients are to be enrolled in Stage 1. If >25 of 31 patients (in the FAS) in 
Stage 1 experience a response to treatment, then enrollment will continue in Stage 2, with up to 
40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a response to treatment, 
no further patients will be enrolled. Thus, a total of up to 71 patients will be enrolled in Phase 2.  
If the total number of patients who experience a response is ≥62 of 71, then the study is considered a 
success. 
Schedule of Events 
The schedule of events is presented in Table 1. 
 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
17


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
17 
Version 1.0 (Original) 
Table 1: 
Schedule of Events (Phases 1 and 2) 
Procedure 
Screening 
Conditioning 
ASCT 
Post-ASCT Follow-up1 
D-28 to -1 
D-1 
D0 
M1 
M2 
D100 
(±7 days) 
D130 
(±7 days) 
Written informed consent2 
X 
 
 
 
 
 
 
Eligibility review 
X 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
HCT-CI 
X 
 
 
 
 
 
 
Cancer history, including history of prior ASCT and other 
treatments 
X 
 
 
 
 
 
 
ECHO or MUGA scan 
X 
 
 
 
 
 
 
Pulmonary function testing3 
X 
 
 
 
 
 
 
Infectious disease screening4 
X 
 
 
 
 
 
 
Pregnancy test5 
X 
 
 
 
 
 
 
ECOG performance status 
X 
 
X 
X 
X 
X 
 
Complete physical examination 
X 
 
 
 
 
 
 
Targeted physical examination 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
 
Vital signs6 
X 
X 
X7 
X 
X 
X 
 
Continuous Holter monitoring 
 
X9 
 
 
 
 
 
12-lead ECG10 
X11 
X11 
 
X 
 
 
 
Hematology12 
X 
Repeat daily until hospital discharge 
 
 
 
Kidney function tests (creatinine, urea, and uric acid) 
 
Daily from the start of tinostamustine 
through Day 3post-ASCT 
 
 
 
 
Clinical chemistries13 
X 
X 
X 
X 
X 
X 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
18


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
18 
Version 1.0 (Original) 
Procedure 
Screening 
Conditioning 
ASCT 
Post-ASCT Follow-up1 
D-28 to -1 
D-1 
D0 
M1 
M2 
D100 
(±7 days) 
D130 
(±7 days) 
Coagulation parameters: PT and/or INR, aPTT 
X 
 
X 
X 
 
X 
 
Urinalysis14 
X 
 
 
 
 
 
 
Tinostamustine administration15 
 
X 
 
 
 
 
 
PK sample collection 
 
X16 
 
 
 
 
 
ASCT17 
 
 
X 
 
 
 
 
Disease assessments 
 
 
 
 
 
 
 
Skeletal survey18 
X 
 
 
 
 
 
 
Bone marrow aspirate and biopsy19 
X 
 
 
 
 
D100 
(±7 days)20 
 
Serum / urine M protein quantitation 
X 
 
 
X 
X 
X 
X 
Immunoglobulin quantitation 
(IgA, IgG, and IgM [required]; IgD, IgE [optional]) 
X 
 
 
X 
X 
X 
X 
Free light chain analysis 
X 
 
 
X 
X 
X 
X 
Disease response assessment21 
X 
 
 
X 
X 
X 
 
Evaluation for MRD-N 
 
 
 
 
 
D100 
(±7 days)20 
 
AE monitoring22 
AEs, including SAEs, are to be documented from the provision of written informed consent through Day 100. 
 
Prior/concomitant medications23 
All medications administered within 28 days before Day 0 through Day 100 are to be documented. 
 
1. 
Patients will be evaluated daily on an inpatient basis until engraftment criteria are met and the patient is discharged from the hospital. Thereafter, study center visits will be 
performed on an outpatient basis. Visit M1: D30  ( ±5days); visit M2: D60  (±5days)  
2. 
Written informed consent is to be obtained before the performance of any study-related procedures. 
3. 
Pulmonary function testing is to include FEV1, FVC, and DLCO. 
4. 
Infectious disease marker testing is to include, at a minimum, human immunodeficiency virus (HIV) types 1 and 2, hepatitis B virus (HBV) panel (HBV surface antigen, 
HBV surface antibody, HBV core antibody, HBV e-antigen), hepatitis C virus (HCV), Treponema pallidum, CMV, and Epstein-Barr virus. 
5. 
Urine or serum pregnancy testing will be performed for women of childbearing potential. Pregnancy testing is to be repeated on study any time pregnancy is suspected. 
6. 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital signs are to be measured after patient is sitting for 3-5 minutes.  
7. 
Perform assessment both pre- and post-treatment. 
8. 
ECGs (12-lead) are to be performed after the patient is supine for 5 minutes. Repeat ECGs as clinically indicated. All ECGs will be reviewed centrally. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
19


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
19 
Version 1.0 (Original) 
9. 
Continuous Holter monitoring will be performed on Day -1, the day of tinostamustine administration. Holter monitoring will commence 15 minutes prior to the start of the 
infusion on Day -1 and will continue through 24 hours following the end of infusion. Patients should be resting comfortably in the supine or semisupine position for 15 
minutes prior to each of the following timepoints: 0 [before start of infusion] then after start of the infusion at 15, 30, 45, and 60 minutes and 3, 6, and 24 hours following the 
start of the infusion. At time 0 and at all time points after infusion, ECGs readings will be extracted in triplicate, with each ECG separated by 5 minutes (±2 minutes), for 
establishment of baseline for the purposes of cardiac safety analyses. The Holter monitor flashcards will be sent to eResearch Technology, Inc., for processing.  
10. 
The Investigator’s interpretation of ECGs is to be used for patient management during the study; the central reader interpretation of ECGs extracted from Holter monitoring 
will be used to determine all ECG data for study endpoints including baseline QTcF interval for cardiac safety analyses and DLTs. 
11. 
A triplicate ECG will be performed during Screening to determine patient eligibility for the study. Furthermore, on Day -1, a triplicate ECG is to be performed before study 
drug administration and a single ECGs will be performed at 30 and 60 minutes after the start of study drug administration for assessment by the site. Another single ECG will 
be performed at visit on day 30 (±5 days). ECGs are to be repeated by the Investigator, as clinically indicated. 
12. 
Hematology parameters minimally include WBC count and differential (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) count, 
hematocrit, hemoglobin, and platelet count. 
13. 
Serum chemistry parameters minimally include alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase, (AST), bicarbonate, 
bilirubin (total, direct, and indirect), calcium, magnesium, chloride, glucose, lactate dehydrogenase (LDH), phosphate, potassium, sodium, and total protein. 
14. 
Urinalysis includes appearance, color, pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, urobilinogen, and occult blood. 
15. 
The tinostamustine dose will be administered one day before ASCT (Day -1), at least 24 hours pre-ASCT.  
16. 
Blood samples for PK are to be collected immediately pre-infusion of tinostamustine and 30, 45, and 60 (±5) minutes and then at 3, 6, and 24 hours (±15 minutes) and then 
48 hours (±30 minutes) after the start of infusion. Blood samples for PK assessment should be collected following the 15-minute supine resting periods described for the 
continuous Holter recordings. PK samples are to be collected from the arm opposite of that used for tinostamustine administration. 
17. 
On Day 1, ASCs will be administered IV according to standard institutional practice. If the CD34+ product is of large volume, the infusion can be given over 2 days. 
18. 
A skeletal survey (plain radiographs, or any other method used as standard care at the site, of the skull, spine, ribs, pelvis, humeri and femora) will be performed at Screening 
if not performed within the previous 3 months. Thereafter, skeletal survey and/or other imaging studies are to be performed as clinically indicated. 
19. 
Bone marrow aspirate and trephine biopsy are to be performed during Screening. Bone marrow aspirate and biopsy are to be repeated during treatment as clinically indicated, 
at the Investigator’s discretion, and at any time CR is suspected.  
20. 
Any patient who achieves a CR will have peripheral blood and bone marrow collected at Day 100 (±7 days) for assessment of evidence of MRD-N via next-generation flow 
cytometry.  
21. 
Disease response will be assessed by the Investigator using the IMWG Criteria. Confirmation should be obtained for biochemical markers but is not necessary for bone 
marrow or imaging studies. There is no specific time interval required between the 2 evaluations, the the confirmatory tests ideally should be performed approximately 
4 weeks after the initial evaluation. 
22. 
AEs will be documented as occurring pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start of the first tinostamustine infusion through 
immediately before the start of autologous stem cell [ASC] infusion); or after ASCT (i.e., after the start of ASC infusion).  
23. 
Concomitant medications will be documented as administered pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start of the first tinostamustine 
infusion through immediately before the start of ASC infusion); or after ASCT (i.e., after the start of ASC infusion). 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
20


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
20 
Version 1.0 (Original) 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AK-DACi 
Alkylating deacetylase inhibitor 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASC 
Autologous stem cell 
ASCT 
Autologous stem cell transplantation 
AST 
Aspartate aminotransferase 
AUC0 12 
Area under the plasma concentration curve from 0 to 12 hours 
AUC0-t 
Area under the plasma concentration curve from time 0 to time t 
CA 
Competent Authorities 
CL/F 
Apparent total clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CoV 
Coefficient of variation 
CR 
Complete response 
CRA 
Clinical Research Associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DLCO 
Carbon monoxide diffusing capacity 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
21


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
21 
Version 1.0 (Original) 
Abbreviation 
Definition 
EDTA 
Ethylenediaminetetraacetic acid 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FLC 
Free light chain 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 
HCT-CI 
Hematopoietic cell transplantation comorbidity index 
HCV 
Hepatitis C virus 
HDACi 
Histone-deacetylase inhibitor 
HIV 
Human immunodeficiency virus 
HPβCD 
Hydroxyl-propyl-β-cyclodextrin 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
Ig 
Immunoglobulin 
IMWG 
International Myeloma Working Group 
IRB 
Institutional review board 
IRC 
Independent Review Committee 
IV 
Intravenous(ly) 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferase 
MI 
Myocardial infarction 
MM 
Multiple myeloma 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
22


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
22 
Version 1.0 (Original) 
Abbreviation 
Definition 
MR 
Minimal response 
MRD-N 
Minimal residual disease-negativity 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
PBSC 
Peripheral blood stem cell 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PR 
Partial response 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SD 
Standard deviation 
SUSAR 
Serious and unexpected suspected adverse reaction 
t1/2 
half-life 
tmax 
Time to maximum plasma concentration 
TRM 
Treatment-related mortality 
ULN 
Upper limit of normal 
US 
United States 
Vd/F 
Apparent volume of distribution  
VGPR 
Very good partial response 
WHO-DD 
World Health Organisation Drug Dictionary 
λz 
Terminal disposition rate constant 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
23


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
24
CCI


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
25
CCI


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
25 
Version 1.0 (Original) 
9.1.5. 
Prior and Concomitant Medications ..................................................... 54 
9.1.6. 
Echocardiogram or Multi-gated Acquisition Scan ............................... 54 
9.1.7. 
Pulmonary Function Testing ................................................................. 55 
9.1.8. 
Screening Serologies............................................................................. 55 
9.1.9. 
Pregnancy Testing................................................................................. 55 
9.2. 
Safety Measurements ......................................................................................... 55 
9.2.1. 
Physical Examination, .......................................................................... 55 
9.2.2. 
Height and Weight ................................................................................ 56 
9.2.3. 
ECOG Performance Status ................................................................... 56 
9.2.4. 
Vital Signs............................................................................................. 57 
9.2.5. 
Holter Monitoring ................................................................................. 58 
9.2.6. 
12-Lead Electrocardiogram .................................................................. 58 
9.2.7. 
Safety Laboratory Tests ........................................................................ 59 
9.2.8. 
Adverse Events ..................................................................................... 60 
9.3. 
Disease Assessments ........................................................................................... 65 
9.3.1. 
Myeloma Protein Measurements in Serum and Urine .......................... 65 
9.3.2. 
Free Light Chain Testing ...................................................................... 66 
9.3.3. 
Bone Marrow Examination ................................................................... 66 
9.3.4. 
Skeletal Survey and Other Imaging Studies ......................................... 66 
9.3.5. 
Assessment of Disease Response ......................................................... 66 
9.3.6. 
Independent Review Committee ........................................................... 68 
9.4. 
Pharmacokinetics ............................................................................................... 69 
10. 
Statistical Analyses......................................................................................................... 70 
10.1. Statistical Basis for Sample Size ....................................................................... 70 
10.2. Statistical and Analytical Plan .......................................................................... 70 
10.2.1. 
General Methods ................................................................................... 71 
10.2.2. 
Analysis Populations............................................................................. 71 
10.2.3. 
Missing Data ......................................................................................... 71 
10.2.4. 
Disposition of Patients .......................................................................... 71 
10.2.5. 
Demographics and Baseline Characteristics ......................................... 71 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
26


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 1.0, 20 March, 2018 
 
CONFIDENTIAL 
26 
Version 1.0 (Original) 
10.2.6. 
Extent of Exposure................................................................................ 72 
10.2.7. 
Prior and Concomitant Medications ..................................................... 72 
10.2.8. 
Efficacy Analyses ................................................................................. 72 
10.2.9. 
Pharmacokinetic Analyses .................................................................... 72 
10.2.10. Safety Analyses..................................................................................... 73 
10.2.11. Interim Analyses ................................................................................... 73 
10.3. Changes to the Planned Statistical Methods ................................................... 73 
11. 
Ethical, Legal, and Administrative Considerations .................................................... 74 
11.1. Good Clinical Practice ....................................................................................... 74 
11.2. Informed Consent .............................................................................................. 74 
11.3. Institutional Review Board/Ethics Committee ................................................ 74 
11.4. Amending the Protocol ...................................................................................... 75 
11.5. Confidentiality .................................................................................................... 75 
11.6. Publication Policy............................................................................................... 75 
12. 
Study Management ........................................................................................................ 76 
12.1. Data Quality Assurance ..................................................................................... 76 
12.2. Case Report Forms and Source Documentation ............................................. 76 
12.3. Monitoring .......................................................................................................... 76 
12.4. Inspections .......................................................................................................... 76 
12.5. Financial Disclosure Reporting Obligations .................................................... 77 
12.6. Archiving Study Records .................................................................................. 77 
13. 
REFERENCES ............................................................................................................... 78 
 
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LIST OF TABLES IN THE TEXT 
Table 1: 
Schedule of Events (Phases 1 and 2) ............................................................................... 17 
Table 2: 
Response Outcomes After ASCT Preceded by Melphalan Conditioning 
(CIBMTR SC17-05 Report) ............................................................................................ 32 
Table 3: 
Pooled Response Outcomes After ASCT Preceded by Melphalan 
Conditioning .................................................................................................................... 32 
Table 4: 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores........................................................... 57 
Table 5: 
Criteria for Determination of Adverse Event Relationship to Study Drug ...................... 62 
Table 6: 
IMWG Response Criteria ................................................................................................ 66 
 
 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Phase 1 
3.1.1.1. 
Primary Objectives 
The primary objectives of Phase 1 of this study are to: 
• Establish the safety, toxicity, and MTD of the tinostamustine conditioning regimen.  
• Identify the RP2D of tinostamustine for use in the Phase 2 portion of the study. 
3.1.1.2. 
Secondary Objectives 
The secondary objective of Phase 1 of this study is to: 
• Investigate the PK of tinostamustine. 
3.1.2. 
Phase 2 
3.1.2.1. 
Primary Objectives 
The primary objectives of Phase 2 of the study are to: 
• Investigate the efficacy of the tinostamustine conditioning regimen at the RP2D. 
• Investigate the safety of the tinostamustine conditioning regimen. 
3.1.2.2. 
Secondary Objectives 
The secondary objective of Phase 2 of this study is to: 
• Evaluate the PK of tinostamustine. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy 
3.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint in Phase 2 of the study is: 
• Objective response rate (ORR): complete response [CR] plus partial response [PR] at 
Day 100 (±7 days) post-ASCT. 
3.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints among patients treated at the RP2D (in Phases 1 and 2) are: 
• ORR and, in patients who achieve CR, minimal residual disease-negativity (MRD-N), as 
determined by next-generation flow cytometry at Day 100 (±7 days) post-ASCT. 
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3.2.2. 
Safety 
The safety endpoint in Phase 1 of the study is: 
• DLTs 
Additional safety endpoints in both Phases 1 and 2 of the study are: 
• Incidence of neutrophil and platelet engraftment failure. 
• Duration of cytopenia (i.e., absolute neutrophil count [ANC] ≤0.5×109/L; platelet count 
≤20×109/L). 
• Cumulative incidence of treatment-related mortality (TRM). 
• Transplant-related non-hematologic Grade 3 toxicity over time through Day 30, stratified 
by hematopoietic cell transplantation comorbidity index (HCT-CI).  
• Incidence of adverse events (AEs) and serious adverse events (SAEs). 
• Change from baseline in standard safety hematology and clinical chemistry test results. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a 2-part, international, multi-center, open-label study of salvage treatment with 
tinostamustine conditioning followed by ASCT in patients with relapsed/refractory MM. (ASCT 
is defined as salvage if the patient had already received a prior ASCT and undergoes a second 
ASCT after evidence of progressive disease [PD].) 
Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of 
defining the DLTs of the tinostamustine conditioning regimen and defining the MTD and RP2D 
for use in the Phase 2 portion of the study. The initial dose of tinostamustine in the Phase 1 
portion of the study is 180 mg/m2, with escalation to 220, 260, and then 300 mg/m2 or higher 
planned. If the 180 mg/m2 dose level is not tolerable, then a lower tinostamustine dose of 
160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, with <33% of patients 
experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may be explored. The 
Safety Review Committee can make a decision to stop dose escalation or explore intermediary 
doses at any time. 
In Phase 2 of the study, all patients will receive tinostamustine at the RP2D administered in 
Phase 1 according to the same schedule.  
Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up 
to 31 patients initially will be enrolled. Recruitment will continue during the evaluation period 
needed for Stage 1 of Phase 2. If ≤25 patients of these initial 31 patients experience a response, 
then no additional patients will be enrolled. However, if >25 patients in Stage 1 of Phase 2 
experience a response, then enrollment in this cohort will continue, with up to 71 patients 
enrolled. In Phase 2 of the study, all patients will receive tinostamustine at the RP2D 
administered in Phase 1 according to the same schedule. 
After provision of written informed consent, patients will be screened for study eligibility within 
28 days before Day 0 (the day of ASCT). Patients who have a minimum of 2×106 CD34+ 
cells/kg cryopreserved and are otherwise determined to be eligible, based on screening 
assessments, will be enrolled and receive the tinostamustine conditioning regimen. The 
tinostamustine dose will be administered 24 hours pre-ASCT (i.e., Day -1).  
On Day 1, ASCs will be administered intravenously (IV) according to standard institutional 
practice.  
Patients will receive standard supportive measures (including growth factor support post-ASCT, 
antimicrobial prophylaxis, red blood cell and platelet transfusion and treatment for neutropenic 
fever) according to standard institutional practice. 
During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 
Day 30 (±5 days) post-ASCT or until all transplant-related toxicity resolves. Patients will be 
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discharged from the study center once the following engraftment criteria are met: 
• Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
• Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days. 
Thereafter, patients are to be followed at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
4.2. 
Justification for the Study Design  
Goals of Phase 1 oncology studies include estimation of the initial safety and tolerability of a 
study drug, establishment of an MTD, and determination of a recommended range of doses for 
evaluation in future clinical studies, based on safety and PK (Ahn, 1998; Gatsonis, Greenhouse, 
1992; Dillman, Koziol, 1992); the primary objectives of the current study are consistent with 
those typical of Phase 1 oncology studies.  
Phase 1 of the study employs a traditional 3+3 dose escalation design. The dose escalation 
scheme to be followed is based on a modified Fibonacci sequence schema, which is commonly 
employed in Phase 1 dose-finding oncology studies (Storer, 1989).  
After identification of the RP2D in the Phase 1 portion of the study, the potential efficacy of 
conditioning with tinostamustine followed by ASCT will be investigated in the Phase 2 portion 
of the study. Phase 2 utilizes a Simon 2-stage minimax design, a common design in Phase 2 
oncology clinical studies by which the expected sample size is minimized if the treatment 
regimen has minimal activity (Simon, 1989).  
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5. 
STUDY POPULATION 
Patients with relapsed/refractory MM who have received prior ASCT after standard first-line 
induction treatment are planned to be enrolled. 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible for study entry: 
1. Patient has MM and: 
a. Has received prior ASCT after standard first-line induction treatment. 
b. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18 months 
in Phase 2. 
Progression Free Interval is defined as the time from date of ASCT to PD. 
c. Received treatment with ≤3 prior lines of therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. 
When patients have undergone sequential phases of treatment without intervening 
progression, such as induction, collection of peripheral blood stem cells, 
transplantation and consolidation/maintenance, this is considered to be 1 line of 
treatment. A new line of therapy is initiated as a result of PD or relapse (Garderet et 
al, 2017). 
2. CR, PR, or minimal response (MR) to salvage chemotherapy, as determined by the 
International Myeloma Working Group (IMWG) criteria.  
3. Is, in the Investigator’s opinion, a candidate for consolidation therapy with tinostamustine 
followed by ASCT. (Note that patients planned to receive tandem ASCT are not eligible 
for the Phase 1 portion of the study.) 
4. Has available autologous PBSC product with CD34 cell dose ≥2×106 cells/kg. The 
product could be from a collection prior to first ASCT or later second collection.  (Note 
that, although not required, in Phase 1, the Investigator should consider enrolling patient 
with a large number of available PBSCs to permit subsequent ASCT, as patients in 
Stage 1 may received a dose lower than that determined to be effective.) 
5. Age 18-75 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score <3 at Screening. 
7. Creatinine clearance ≥40 mL/min, as determined by a local laboratory using the 
Cockcroft-Gault equation within 28 days before ASCT. 
8. Left ventricular ejection fraction (LVEF) ≥40% within 28 days before ASCT. 
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9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), 
forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) >50% 
predicted within 28 days before ASCT. 
10. Adequate liver function, as defined by an alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN) and bilirubin ≤1.5 × 
ULN within 28 days before ASCT.  
11. Potassium within the local laboratory’s normal range. (Potassium supplementation is 
permissible.) 
5.2. 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study entry: 
1. History of central nervous system (CNS) disease involvement. 
2. Primary or secondary plasma cell leukemia at any time point prior to transplant 
2. Myocardial infarction (MI) or stroke within 6 months before Screening.  
3. Uncontrolled acute infection. 
4. HCT-CI >6 points. 
5. Concurrent malignant disease with the exception of treated basalioma/spinalioma of the 
skin or early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment 
for other malignancies (not listed above) must have been terminated at least 24 months 
before registration and no evidence of active disease shall be documented since then. 
6. Major coagulopathy or bleeding disorder. 
7. Other serious medical condition that could potentially interfere with the completion of 
treatment according to this protocol or that would impair tolerance to therapy or prolong 
hematological recovery. 
8. Lack of cooperation to allow study treatment as outlined in this protocol. 
9. Pregnancy or lactating female patients.  
10. The use of any anti‐cancer investigational agents within 21 days prior to the expected 
start of trial treatment and interval of 14 days to last administration of salvage treatment. 
11. Receiving treatment with drugs known to prolong the QT/QTc interval. 
12. QTc interval (Fridericia’s formula) >450 msec, based on the mean of triplicate Screening 
12-lead ECGs.   
 
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5.3. 
Source of Patients 
This will be a multinational, multicenter study. Each study center is required to obtain local 
Institutional Review Board (IRB)/Ethics Committee (EC) and national regulatory approval to 
conduct the study before enrollment of patients may commence. Patients meeting the entry 
criteria who are known or referred to the study center will be eligible for enrollment. 
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6. 
STUDY CONDUCT 
6.1. 
Patient Identification and Enrollment 
To ensure accurate and timely monitoring of patient enrollment, the following procedures will be 
implemented: 
• Patients who are candidates for enrollment into the study will be assigned a sequential 
and unique patient number by the Investigator after the patient has provided written 
informed consent. Once a patient number has been assigned, it cannot be reused. 
• Patients who have provided written informed consent will be evaluated for eligibility by 
the Investigator to ensure that the entry criteria (see Section 5.1 and Section 5.2) have 
been satisfied and that the patient is eligible for participation in this clinical study. An 
eligibility form will be provided by the Sponsor, or designee for this evaluation. 
• The Investigator or the Investigator’s research staff will provide eligibility information to 
the Sponsor or designee. After confirmation, the Sponsor or designee will provide the 
Investigator with written verification of each patient’s enrollment. 
• No patient may be enrolled prior to confirmation of a patient’s eligibility by the Sponsor 
or designee. 
• Patients who are enrolled but not treated with tinostamustine followed by ASCT will be 
replaced.  
• Investigators will be notified by the Sponsor or designee when enrollment in a given dose 
cohort / study part is closed and enrollment into the next dose cohort / study part can 
begin. (Investigators will be consulted in all dose escalation decisions.) 
• Investigators will be notified by the Sponsor or designee if the study is placed on 
administrative hold, when it is completed, or is closed to further patient enrollment. 
6.2. 
Patient Management 
All patients must provide written informed consent before any samples are collected or 
evaluations performed in this study that are not part of standard patient care. Patients will be 
evaluated for study eligibility during the Screening period, within 28 days before baseline 
(Day 1; the Day of ASCT).  
Patients who are determined to be eligible, based on Screening assessments, will return to the 
clinic to receive the tinostamustine conditioning regimen; the tinostamustine dose will be 
administered 24 hours pre-ASCT (on Day -1). 
On Day 1, ASCs will be administered IV according to standard institutional practice.  
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During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 
Day 30 (±5 days) post-ASCT or until all transplant-related toxicity resolves. Patients will be 
discharged from the study center once engraftment criteria are met (see Section 8.3). 
Thereafter, patients are to be followed at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
6.3. 
Patient Adherence 
All patients are required to adhere to the protocol-specified dosing and visit schedules. If a 
patient misses a scheduled visit, attempts should be made to reschedule the visit within the visit 
windows specified in Table 1. Failure to attend scheduled study visits may result in 
discontinuation from the study. 
6.4. 
Treatment Discontinuation Criteria 
Once tinostamustine has been infused it will be medically negligent to stop transplant and 
supportive therapy for the particular patient.  In the event of consent withdrawal during or 
following conditioning or the development of complications that, in the Investigator’s opinion, 
puts the patient at risk with continued protocol-specified treatment, the Medical Monitor should 
be contacted immediately to discuss management of the patient.  
6.5. 
Study Discontinuation Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Patient non-adherence to protocol requirements. 
• Patient unwillingness to continue in the study. 
• Any other reason, based upon the medical judgment of the Investigator. 
The reason for study withdrawal is to be documented in the patient’s source documents and 
electronic case report form (eCRF). 
6.6. 
Study Completion 
A patient is considered to have completed the study if they complete the Day 100 (±7 days) visit 
and a confirmatory response assessment at D130 (±7 days) visit, the latest.  
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6.7. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest the study 
should be halted, then this can happen only after appropriate consultation between the Sponsor 
and Investigator. Conditions that may warrant study termination include, but are not limited to: 
• The discovery of any unexpected, significant, or unacceptable risk to the patients enrolled in 
the study. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence to the protocol requirements. 
• A decision on the part of the Sponsor to suspend or discontinue development of 
tinostamustine. 
6.8. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study. The Investigator at each 
study center is responsible for ensuring the accuracy and completeness of all research records, 
the accountability of study drug, and the conduct of clinical and laboratory evaluations as 
outlined in the protocol. The Investigator is responsible for ensuring that the clinical study is 
performed in accordance with the Declaration of Helsinki and the International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidance documents. 
6.9. 
Safety Committee 
A Safety Committee will be involved in the conduct of this study. The Safety Committee will be 
comprised of Sponsor personnel, the Medical Monitor, the Investigator or representative thereof 
at each active study center, and a biostatistician (as needed). Ad hoc participants may be part of 
the committee at the request of the Sponsor or other Safety Committee members. The Safety 
Committee has the responsibility for monitoring the clinical study’s progress and the safety of 
the participating patients. The Safety Committee will evaluate study conduct during the course of 
the clinical study, based upon data defined for this clinical study.  
In Phase 1, the Safety Committee will review all safety data from all patients enrolled in each 
cohort to confirm any DLTs that were experienced and make a determination regarding 
enrollment in the next cohort. If a DLT necessitates enrollment of additional patients into a 
cohort, the Safety Committee will review all of the safety data for that cohort after those 
additional patients before a determination regarding enrollment in the next cohort is made. Based 
on evaluation of the data, the Safety Committee may decide that enrollment at an intermediate 
dose level not specified in this protocol may take place.  
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In addition, after identification of the MTD, the Safety Committee will review all safety data 
collected to date to confirm that no unexpected, significant, or unacceptable risk to patients 
enrolled in the study has been discovered.  
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Clinical Study Protocol EDO-S101-1004 
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CONFIDENTIAL 
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Version 1.0 (Original) 
 
7.5. 
Study Drug Dose 
In Phase 1 of the study, the starting dose of tinostamustine is 180 mg/m2, with escalation to 220, 
260, and then 300 mg/m2 planned. If the 180 mg/m2 dose level is not tolerable, then a lower 
tinostamustine dose of 160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, 
with <33% of patients experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may 
be explored. The Safety Review Committee can make a decision to stop dose escalation or 
explore intermediary doses at any time. 
In Phase 2, patient will receive tinostamustine at the RP2D identified in Phase 1.  
7.5.1. 
Dose Escalation Procedure 
In Phase 1, up to 3 patients initially are to be enrolled in each cohort. The first patient enrolled in 
the initial cohort must complete the study through engraftment without a ≥Grade 3 toxicity or 
through 30 days post-ASCT without a DLT, whichever occurs first, before additional patients 
may be enrolled in that initial cohort. (If the first patient experiences a DLT, then a lower dose 
will be explored for the second patient and so on.) 
• If the first patient does not experience a DLT (see Section 7.5.2) or experiences 
engraftment without a ≥Grade 3 toxicity, the next 2 patients may be enrolled 
simultaneously. 
After 3 patients in a cohort complete the study through engraftment without a ≥Grade 3 toxicity 
or through 30 days post-ASCT without a DLT, whichever occurs first, and have safety 
evaluations performed through that time, and: 
• None of these 3 patients experience a DLT (see Section 7.5.2), then enrollment of the 
next cohort may commence with approval from the Safety Committee. 
• 1 of 3 patients within a cohort experiences a DLT (see Section 7.5.2), then up to 
3 additional patients are to be enrolled sequentially at that dose level. If none of the 
additional 3 patients has a DLT (i.e., 1 of 6 patients has a DLT), then enrollment at the 
next scheduled dose may commence with approval from the Safety Committee. 
• If ≥2 patients within a cohort experience a DLT (see Section 7.5.2), then the DLT dose 
level will have been reached and the previous lower dose level will be considered the 
MTD. (If ≥2 patients in the initial dose cohort experience DLTs, then the dose will be 
reduced to one level lower and the same procedure will be followed.) 
A total of 6 patients are planned to be treated at the MTD to confirm the RP2D before enrollment 
of patients in Phase 2 of the study. If the MTD is not confirmed at this stage, the dose will be 
reduced to one level lower and the same procedure will be followed. 
Note that enrollment in the next dose cohort can begin only when the last patient enrolled in the 
current dose cohort completes the study through engraftment without a ≥Grade 3 toxicity or 
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CONFIDENTIAL 
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through 30 days post-ASCT without a DLT, whichever occurs first,, provided that <2 patients in 
the current dose cohort experienced a DLT.  
Although decisions regarding dose escalation will be made based on review of data through 
Day 30 post-ASCT, safety data will also be collected from all patients continuing in the study 
and this will be reviewed periodically by the Safety Committee. Any detected toxicity may 
necessitate further refinement of the RP2D. 
7.5.2. 
Definition of Dose-limiting Toxicity 
Toxicity will be assessed by the Investigator using the US NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version 4.03. The centralized laboratory assessment of ECGs will 
be used for the determination of DLT. 
In Phase 1 of the study, DLT is defined as the occurrence of any of the following events 
occurring within 30 days post-ASCT that are considered by the Investigator to be at least 
possibly related to tinostamustine: 
• Delayed engraftment (>30 days after ASCT). Engraftment will be considered delayed if 
the subject has not met criteria for both neutrophil and platelet engraftment:  
- Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
- Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days.  
• QTcF >500 msec or >60 msec increase from baseline, with a duration of >30 minutes, 
based on the mean of triplicate 12-lead ECGs, or ≥Grade 3 QTcF interval prolongation 
accompanied by ventricular arrhythmia.  
Baseline QTcF interval will be the mean value determined during triplicate ECG(s) at 
Day -1 (-1), before study drug administration confirmed by the cental laboratory. 
• Grade 4 non-hematologic toxicity 
• Grade 3, non-hematologic toxicity related to treatment, with the exception of: 
- Nausea or vomiting  
- Diarrhea  
- Fatigue, dehydration, or glucose intolerance 
- Skin rash, dry skin, or pruritus responsive to topical or systemic steroids 
- Fever (>40ºC for ≤24 hours) 
- Infection 
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13 May 2020
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7.8.1. 
Prohibited Medications 
The following medications and treatments are prohibited during study participation: 
• Any investigational agent or device other than tinostamustine, including agents that are 
commercially available for indications other than MM that are under investigation for the 
treatment of MM. 
• Any anti-neoplastic treatment with activity against MM.  
• Medications known to prolong the QT/QTc interval, will be excluded. The use of other 
concomitant medications that present a low risk of QT/QTc prolongation may be 
considered, with the approval of the Medical Monitor. (Refer to the crediblemeds list of 
drugs with known risk of TdP: http://crediblemeds.org.) 
7.8.2. 
Permitted Medications and Supportive Therapies 
Medications and treatments other than those specified in Section 7.8.1, including palliative and 
supportive care for disease-related symptoms, are permitted during the study. Patients should be 
closely monitored, and treatment is to be instituted for disease-related symptoms, as appropriate. 
Patients may receive the following supportive care:   
• IV hydration and anti-emetics, in accordance with institutional guidelines. 
• Growth factor support with pegfilgrastim or equivalent agent post-ASCT, in accordance 
with institutional guidelines.  
• Standard supportive care, in accordance with institutional guidelines, including blood 
product transfusions, antimicrobial prophylaxis (e.g., anti-bacterial, Pneumocystis carinii, 
anti-fungal, herpes simplex virus/varicella zoster virus), and treatment for febrile 
neutropenia. 
• Bisphosphonates may be administered after ASCT according to local institutional 
practice. 
• After adequate blood count recovery (ANC >1.0×109/L and platelet count >80×109/L) as 
well as resolution of mucositis and fever, if present, radiation may be administered for the 
following indications after consultation with the Medical Monitor: 
- Palliation of pain from bone lesions 
- Prevention of pathologic fractures 
- Relief of spinal cord compression or nerve root compression 
The radiation oncologist is to determine the dose and duration of radiation to be 
administered. Radiation to the liver or lungs should be avoided.  
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CONFIDENTIAL 
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7.9. 
Blinding 
This is an open-label study; no blinding methods will be employed. 
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8. 
TRANSPLANT PROCEDURES 
8.1. 
Conditioning 
See Section 7.6 for details regarding tinostamustine preparation and administration. 
8.2. 
ASCT Infusion 
Patients will receive ASCs on Day 1. The ASCs will be infused via a central venous catheter 
using standard blood infusion tubing, per standard institutional practice. 
8.3. 
Engraftment 
During in-patient hospitalization, patients will be assessed daily for hematologic engraftment, 
starting on the first day the ANC is <0.5×109/L until and including the day engraftment criteria 
are met, as follows: 
• Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
• Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days. 
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9. 
STUDY ASSESSMENTS 
9.1. 
Baseline Assessments 
9.1.1. 
Informed Consent 
All patients must provide written informed consent before any samples are collected or 
evaluations performed in this study that are not part of standard patient care.  
9.1.2. 
Demographics 
Patient demographics, including age, sex, race, and ethnicity, are to be documented in the source 
documents and in the eCRF at Screening.  
9.1.3. 
Medical History, Including Cancer History 
A complete medical history, including prior and concomitant illnesses and conditions as well as 
prior surgeries and other procedures, is to be documented in the source documents and in the 
eCRF at Screening. MM history, including the date of diagnosis and details regarding prior 
ASCT and all other previous treatment for MM and best response to such treatments, also is to 
be documented and recorded in the eCRF. 
9.1.4. 
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) 
The HCT-CI is a validated comorbidity index that comprises 17 different categories of organ 
dysfunction (Sorror et al. 2007; Maruyama et al. 2007; Barba et al. 2010; Frina et al. 2009). 
Positive findings are summated into a total score. The HCT-CI provides information with regard 
to the overall as well as non-relapse mortality risk a patient is likely to experience after SCT. 
HCT-CI score is to be documented in the source documents and in the eCRF at Screening.  
The HCT-CI is accessible at:  http://www.hctci.org/Home/Calculator.  
9.1.5. 
Prior and Concomitant Medications 
All prior medications and supplements the patient received within 28 days before baseline and all 
medications and supplements the patient receives through Day 100 are to be documented in the 
source documents and in the eCRF. Concomitant medications will be documented as 
administered pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start 
of the first tinostamustine infusion through immediately before the start of ASC infusion); or 
after ASCT (i.e., after the start of ASC infusion). 
9.1.6. 
Echocardiogram or Multi-gated Acquisition Scan 
LVEF is to be determined by multi-gated acquisition scan or echocardiography during 
Screening. 
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9.1.7. 
Pulmonary Function Testing 
The following PFTs are to be measured during Screening 
• FEV1 
• FVC 
• DLCO 
Patients who have difficulty making an appropriate seal on the mouthpiece to perform PFTs 
effectively should be fitted with a facial mask for PFT measurements. 
9.1.8. 
Screening Serologies 
Blood samples for infectious disease marker testing, including, at a minimum, human 
immunodeficiency virus (HIV) types 1 and 2, hepatitis B virus (HBV) panel (HBV surface 
antigen, HBV surface antibody, HBV core antibody, HBV e-antigen), hepatitis C virus (HCV), 
Treponema pallidum, cytomegalovirus, and Epstein-Barr virus, are to be collected during 
Screening. Any patient with a positive result is not eligible for study participation.  
9.1.9. 
Pregnancy Testing 
Serum or urine β-human chorionic gonadotropin (hCG) pregnancy testing is to be performed for 
female patients of childbearing potential (i.e., premenopausal or not surgically sterile) during 
Screening. Any patient with a positive result is not eligible for study participation. Pregnancy 
testing is to be repeated any time pregnancy is suspected.  
9.2. 
Safety Measurements 
9.2.1. 
Physical Examination, 
Physical examinations are to be performed at each study center visit. Complete physical 
examinations are to be performed at the time points designated in Table 1. The complete physical 
examination includes assessment of the following: 
• General appearance 
• Head, eyes, ears, nose, and throat  
• Cardiovascular system 
• Respiratory system 
• Gastrointestinal system (abdomen) 
• Lymphatic system 
• Musculoskeletal system 
• Skin 
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• Psychiatric 
• Neurological – A complete neurologic examination, including assessment of mental 
status, memory, cranial nerves, motor function, and reflexes, is to be performed as part of 
the complete physical examination.  
Targeted (i.e., symptom-directed) physical examinations are to be conducted at the time points 
designated in Table 1. 
Abnormal physical examination findings that are considered by the Investigator to be clinically 
significant are to be reported as an AE, if the finding represents a change from baseline. 
9.2.2. 
Height and Weight 
Height is to be measured for all patients during Screening. 
Body weight is to be measured during Screening and at the time points designated in Table 1. 
The patient’s height documented during Screening and weight documented prior to the 
commencement of tinostamustine on Day -1 are to be used to calculate the tinostamustine dose.  
9.2.3. 
ECOG Performance Status 
ECOG performance status is to be determined at the time points designated in Table 1. The 
ECOG performance status scale, with corresponding Karnofsky performance status score 
equivalents, is presented in Table 4. 
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Table 4: 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores 
ECOG1 
Karnofsky2 
Score 
Criterion 
% 
Criterion 
0 
Normal activity 
100 
Normal; no complaints; no evidence of 
disease 
 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
Symptoms but ambulatory 
80 
Normal activity with effort; some signs or 
symptoms of disease 
 
 
70 
Cares for self; unable to carry on normal 
activity or do active work 
2 
In bed <50% of time 
60 
Requires occasional assistance but is able 
to care for most of his/her needs 
 
 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed >50% of time 
40 
Disabled, requires special care and 
assistance 
 
 
30 
Severely disabled; hospitalization is 
indicated though death is not imminent 
4 
100% bedridden 
20 
Very sick; hospitalization is necessary 
 
 
10 
Moribund; fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
1 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
2 
Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale:  an examination of its reliability 
and validity in a research setting. Cancer. 1984;53:2002-2007. 
9.2.4. 
Vital Signs 
Vital signs, including blood pressure, pulse and respiration rates, and body temperature, are to be 
measured at the time points designated in Table 1. Pulse rate and blood pressure will be 
measured with the patient in a sitting position after a 5-minute rest. 
Vital signs abnormalities that are considered by the Investigator to be clinically significant are to 
be reported as AEs, if the finding represents a change from baseline. 
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9.2.5. 
Holter Monitoring 
Continuous Holter monitoring will be performed on Day -1, the day of tinostamustine 
administration. Holter monitoring will commence 15 minutes prior to the start of the infusion on 
Day -1 and will continue through 24 hours following the end of infusion. 
Patients should be resting comfortably in the supine or semisupine position for 15 minutes prior 
to each of the following timepoints: 0 [before start of infusion] then after start of the infusion at 
15, 30, 45, 60 and 75 minutes and 3, 6, and 24 hours following the start of the infusion. 
At time 0 and at all time points after infusion, ECGs readings will be extracted for establishment 
of baseline and for the purposes of Dose Limiting Toxicities determination and for cardiac safety 
analyses. 
The Holter monitor flashcards will be sent to eResearch Technology, Inc., for processing. The 
analysis methodology will be described in a separate ECG cardiac safety statistical analysis plan. 
Note that because the ECG recordings are stored on flashcards, results will not be available in 
“real time” at the study center. 
The ECGs extracted from the Holter monitoring will be used for the determination of DLTs. 
9.2.6. 
12-Lead Electrocardiogram 
A triplicate ECG will be performed during Screening to determine patient eligibility for the 
study. Furthermore, on Day -1 (-1 day), a triplicate ECG is to be performed before study drug 
administration and a single ECGs will be performed at 30 and 60 minutes after the start of study 
drug administration for assessment by the site. Another single ECG will be performed at visit on 
D30 (±5 days). ECGs are to be repeated by the Investigator, as clinically indicated. 
ECGs (12-lead) are to be performed in after the patient is supine for 5 minutes.  
All ECGs will be reviewed centrally. The Investigator or the Sponsor may request expedited 
central review of ECGs, as clinically indicated. 
The Investigator’s interpretation of ECGs is to be used for patient management during the study; 
the central reader interpretation of ECGs extracted from Holter monitoring will be used to 
determine all ECG data for study endpoints including baseline QTcF interval for cardiac safety 
analyses and DLTs. 
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9.2.7. 
Safety Laboratory Tests 
9.2.7.1. 
Hematology, Serum Chemistries, and Urinalysis 
Blood samples are to be collected for assessment of hematology, coagulation studies, and clinical 
chemistry parameters  and urine samples for urinalysis, according to the schedule defined in 
Table 1. Laboratory samples are to be collected after vital signs are measured. 
The following safety laboratory parameters will be measured: 
Hematology 
 
• 
Hematocrit 
• 
Neutrophils 
• 
Hemoglobin 
• 
Lymphocytes 
• 
Red blood cell count 
• 
Monocytes 
• 
White blood cell count 
• 
Eosinophils 
• 
Platelet count 
• 
Basophils 
Serum Chemistries 
 
• 
ALT 
• 
Alkaline phosphatase 
• 
AST 
• 
Bicarbonate 
• 
Bilirubin (total, direct, and indirect) 
• 
Calcium 
• 
Magnesium 
• 
Chloride 
• 
Glucose 
• 
Lactate dehydrogenase 
• 
Phosphate 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Creatinine* 
• 
Blood urea nitrogen 
• 
Uric acid 
 
*To be fractionated if abnormal. 
Coagulation Studies 
 
• 
Prothrombin time and/or International 
normalized ratio 
• 
Activated partial thromboplastin time 
 
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Urinalysis 
 
• 
Color 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Blood 
 
Safety laboratory tests may be repeated as necessary during treatment at a schedule determined 
by the Investigator, based on the patient’s clinical status.  
Laboratory abnormalities that are considered by the Investigator to be clinically significant are to 
be reported as AEs, if the finding represents a change from baseline. 
9.2.8. 
Adverse Events 
9.2.8.1. 
Definitions 
9.2.8.1.1. Adverse Event 
An AE is defined in the ICH Guideline for GCP as “any untoward medical occurrence in a 
patient or clinical investigation patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment” (ICH E6:1.2). 
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) should 
be considered an AE if there is either an increase in severity, frequency, or duration of the 
condition or an association with significantly worse outcomes. 
Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AEs. 
In the case of death, only record “Fatal” for the event causing death. AEs that are ongoing at the 
end of the study or time of death are to be noted as “continuing.” Classification of AEs is to be 
done by the Investigator according to the NCI CTCAE, version 4.03. 
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual patient represents a significant change from baseline. In general, 
abnormal laboratory findings without clinical significance (based on the Investigator’s judgment) 
should not be recorded as AEs; however, laboratory value changes requiring therapy are 
considered AEs. 
9.2.8.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of safety reporting, “reasonable possibility” and/or at least 
possibly related means there is evidence to suggest a causal relationship between the drug and 
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the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by a drug. 
9.2.8.1.3. Serious Adverse Event 
An AE or suspected adverse reaction 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 (i.e., places the patient at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definitions for 
SAEs. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any AE that 
does not meet one of the definitions of serious (i.e., emergency room visit, outpatient surgery, or 
requires urgent investigation) may be considered by the Investigator to meet the “important 
medical event” criterion for classification as an SAE. 
9.2.8.1.4. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, if 
an Investigator’s Brochure is not required or available, is not consistent with the risk information 
described in the General Investigational Plan or elsewhere in the current application, as 
amended.  
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9.2.8.1.5. Serious and Unexpected Suspected Adverse Reaction 
A serious and unexpected suspected adverse reaction (SUSAR) is any event that meets all 3 of 
the following definitions: 
1) suspected adverse reaction (Section 9.2.8.1.2); 
2) serious (Section 9.2.8.1.3); and  
3) unexpected (Section 9.2.8.1.4). 
9.2.8.2. 
Adverse Event Assessment 
All AEs will be collected and recorded from the time written informed consent is obtained 
through Day 100 (±7 days), or after the end of the study, if thought to be related to study drug. 
This includes AEs the patient reports spontaneously, those observed by the Investigator, and 
those elicited by the Investigator in response to open-ended questions during scheduled study 
visits.  
Each AE is to be assessed by the Investigator with regard to the following categories. 
Serious/Non-Serious 
AEs that meet the criteria specified in Section 9.2.8.1 are to be considered serious. 
Relationship to Study Drug 
The relationship of each AE to study drug is to be assessed by the Investigator according to 
categories in Table 5. 
Table 5: 
Criteria for Determination of Adverse Event Relationship to Study Drug 
Relationship Between Study Drug and AE: 
AE (is): 
Category 
None 
Unlikely 
Possibly 
Likely 
Definitely 
Clearly the result of an external factor 
Yes 
No 
No 
No 
No 
Probably/possibly the result of another 
factor 
No 
Yes 
Yes 
No 
No 
Has a chronological relationship with the 
time of administration and/or represents a 
known reaction to Study Drug 
No 
No 
Yes 
Yes 
Yes 
Disappears or decreases after 
discontinuation of the Study Drug 
NA 
NA 
NA 
Yes 
Yes 
Recurs on renewed administration 
(re-challenge) 
No 
No 
NA 
NA 
Yes or 
NA** 
**A re-challenge is not required; if done, re-challenge would be expected to be positive. 
NA = not applicable 
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Intensity 
The intensity of each AE is to be assessed by the Investigator according to the NCI CTCAE, 
version 4.03. If the AE is not included in the NCI CTCAE, version 4.03, then the Investigator is 
to determine the intensity of the AE according to the following criteria: 
• Mild (Grade 1): Asymptomatic or mild symptoms:  clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate (Grade 2): Minimal, local, or non-invasive intervention indicated; limited age-
appropriate instrumental activities of daily living. 
• Severe (Grade 3): Severe or medically significant but not immediately life threatening:  
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living; incapacitating with inability to work or perform normal daily 
activity. 
• Life-threatening (Grade 4): consequences:  urgent intervention indicated.  
• Death (Grade 5) related to an AE. 
9.2.8.3. 
Recording Adverse Events 
All AEs occurring from the from the time written informed consent is obtained through the Day 
100 (±7 days) visit are to be recorded in the source documents and in the eCRF. AEs will be 
documented as occurring pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., 
after the start of the first tinostamustine infusion through immediately before the start of ASC 
infusion); or after ASCT (i.e., after the start of ASC infusion). All AE reports are to contain the 
following details regarding the AE:  a brief description, onset date, duration, intensity, treatment 
required, relationship to study drug, study drug action taken, outcome, and whether the event is 
classified as serious. 
9.2.8.4. 
Reporting Serious Adverse Events 
SAEs will be collected and recorded throughout the study period, beginning with the signing of 
the informed consent form (ICF) through the Day 100 (±7 days) visit, or after the end of the 
study if thought to be related to study drug.  
The Investigator must report all SAEs to the Sponsor within 24 hours of discovery.  
A completed SAE report is to be sent to the Medical Monitor’s attention within 24 hours of 
discovering the event. The initial report should include at least the following information: 
• Patient’s ID number; 
• Description and date of the event; 
• Criterion for serious; and 
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• Preliminary assignment of causality to study drug.  
The Medical Monitor will contact the Investigator via telephone for follow-up information 
regarding the SAE, as appropriate. 
The Investigator, or designated party, should notify the appropriate IRB/EC of SAEs occurring at 
the study center and other AE reports received from the Sponsor, in accordance with local 
procedures and statutes. 
SAEs that are considered as possible or probably related to the investigational product, and as 
unexpected (i.e., SUSARs), will be reported to the concerned Competent Authorities (CAs) and 
IRBs/ECs by the Sponsor or Sponsor’s designee as required by applicable local regulations. Per 
regulation, any fatal or life-threatening SUSAR will be reported to the CAs/IRBs/ECs within 
7 calendar days, and additional information within an additional 8 calendar days. The Sponsor or 
Sponsor’s designee is required to submit any other SUSAR to the CAs/IRBs/ECs within 
15 calendar days of notification. The Sponsor or its designee is also responsible for notifying the 
investigational sites of all expedited SAEs. The Investigator must keep copies of all expedited 
SAE information including correspondence with the Sponsor on file.  
9.2.8.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be at least 
possibly related to study drug either until resolution or the Investigator assesses them as chronic 
or stable. This follow-up may extend after the end of the study. 
9.2.8.6. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB/EC all unanticipated problems involving 
risks to patients. This includes death from any cause and all SAEs reasonably or possibly 
associated with the use of Study Drug according to the IRB/EC’s procedures.  
The Sponsor will assess the severity and frequency of adverse drug reactions in adults versus 
pediatric patients, and will submit findings annually in the Development Safety Update 
Report/Annual Report. 
9.2.8.7. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only in 
the event of an emergency. The Investigator or other physician in attendance in such an 
emergency must contact the Medical Monitor as soon as possible to discuss the circumstances of 
the emergency. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the patient 
should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be noted in the eCRF. 
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9.2.8.8. 
Pregnancy 
Pregnancy is considered unlikely in this study, given the population of patients to be enrolled. 
Nonetheless, pregnancies occurring within 12 months after the patient’s last dose of 
tinostamustine will not be considered serious, but are to be reported using the same procedures as 
for SAEs described in Section 9.2.8.4.  
The patient is to be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling. 
The Investigator will follow the patient until completion of the pregnancy, and must notify the 
Medical Monitor of the outcome within 5 days. The Investigator will provide this information as 
a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such. 
Furthermore, all neonatal deaths that occur within 30 days of birth are to be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to tinostamustine should also be reported. 
9.3. 
Disease Assessments 
9.3.1. 
Myeloma Protein Measurements in Serum and Urine 
9.3.1.1. 
Serum 
Blood samples for quantitation of immunoglobulin (Ig) (IgA, IgG, and IgM are required; IgD 
and IgE are optional) and M-protein and assessment of M-protein by immunofixation in serum 
are to be collected from all patients at the time points designed in Table 1. Note that in the case 
of IgA MM, MM IgA values should be used. 
All samples will be analyzed by the local laboratory. Assessments of response will be evaluated 
by two independednt reviewers.  
9.3.1.2. 
Urine 
Twenty-four hour urine samples for quantitation of M-protein and assessment of M-protein by 
immunofixation are to be collected from all patients during Screening. For patients with positive 
findings at Screening, such samples also are to be collected at the time points designed in 
Table 1. Patients with negative Screening results need not provide urine samples for M-protein 
quantitation and assessment after Screening.  
All samples will be analyzed by the local laboratory. Assessments of response will be evaluated 
by two independednt reviewers.  
 
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9.3.2. 
Free Light Chain Testing 
Serum samples for free light chain (FLC) testing are to be collected from all patients during 
Screening and at the time points designed in Table 1. The free kappa/lambda ratio is to be 
recorded in the eCRF. 
A serum sample for FLC testing also is to be collected in order to confirm stringent complete 
response (sCR). 
9.3.3. 
Bone Marrow Examination 
Bone marrow aspiration to be performed for all patients during Screening, and for patients who 
achieve a CR, on Day 100 (±7 days) post-ASCT. Bone marrow aspiration and biopsy are to be 
repeated during treatment as clinically indicated. 
Approximately 5mL of the same sample (i.e., “first-pull”), collected in 
ethylenediaminetetraacetic acid (EDTA) tubes, will be used for assessment of MRD-N using 
next-generation flow cytometry.  
9.3.4. 
Skeletal Survey and Other Imaging Studies 
Skeletal surveys (plain radiographs, or any other method used as standard care at the site, of the 
skull, spine, ribs, pelvis, humeri and femora) are to be performed during Screening. If a skeletal 
survey has been performed within 3 months before Baseline, then this evaluation need not be 
repeated during Screening.  
A skeletal survey is to be repeated during the study as clinically indicated.  
Other appropriate imaging studies (e.g., magnetic resonance imaging, CT, X-ray) to evaluate the 
patient’s disease are to be performed during Screening per standard of care, as determined by the 
Investigator. Appropriate imaging studies are to be repeated as necessary to confirm CR.  
9.3.5. 
Assessment of Disease Response 
The Investigator will perform tests that will allow evaluation of response to therapy according to 
the IMWG Criteria, as outlined in Table 6. Patients who are determined to have CR are then to 
have additional tests performed that will allow further characterization of the CR.  
Assessment of disease response using non-invasive procedures will be performed at the time 
points designed in Table 1. Appropriate imaging studies and bone marrow aspirates/biopsies 
must be repeated only in patients suspected of having a CR, based on non-invasive procedures. 
Table 6: 
IMWG Response Criteria 
Response 
IMWG Criteria 
Complete response (CR)1 
• 
Negative immunofixation of serum and urine, and 
• 
Disappearance of any soft tissue plasmacytomas, and 
• 
 <5% plasma cells in bone marrow 
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Response 
IMWG Criteria 
Stringent complete response (sCR) 
CR as defined above plus 
• 
Normal FLC ratio, and 
• 
Absence of clonal plasma cells (PC) by 
immunohistochemistry or 2-4 color flow cytometry. 
Immunophenotypic CR 
Stringent CR plus 
• 
Absence of phenotypically aberrant PC (clonal) in bone 
marrow (BM) with a minimum of one million of total BM 
cells analyzed by multiparametric flow cytometry (with >4 
colors) 
Molecular CR 
CR plus 
• 
Negative allele-specific oligonucleotide-polymerase chain 
reaction (ASO-PCR), sensitivity 10-5 
Very good partial response (VGPR)1 
• 
Serum and urine M-component detectable by immunofixation 
but not on electrophoresis, or 
• 
≥90% or greater reduction in serum M-component plus urine 
M component <100 mg per 24 hours 
Partial response (PR) 
• 
≥50% reduction of serum M-protein and reduction in 24-h 
urinary M-protein by ≥90% or to <200 mg per 24 hours 
• 
If the serum and urine M-protein are unmeasurable a ≥50% 
decrease in the difference between involved and uninvolved 
FLC levels is required in place of the M-protein criteria 
• 
If serum and urine M-protein are unmeasurable, and serum 
free light assay is also unmeasurable, ≥50% reduction in bone 
marrow plasma cells is required in place of M-protein, 
provided baseline percentage was ≥30% 
• 
In addition to the above criteria, if present at Baseline, ≥50% 
reduction in the size of soft tissue plasmacytomas is also 
required 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease. 
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Response 
IMWG Criteria 
Progressive disease (PD)2 
• 
Increase of 25% from lowest response value in any one or 
more of the following: 
• 
Serum M-component (absolute increase must be ≥0.5 g/dL) 
and/or 
• 
Urine M-component (absolute increase must be ≥200 mg/24 
hours) and/or 
• 
Only in patients without measurable serum and urine M 
protein levels: the difference between involved and 
uninvolved FLC levels (absolute increase must be >10 mg/dL) 
• 
Only in patients without measurable serum and urine M 
protein levels and without measurable disease by FLC levels, 
bone marrow plasma cell percentage (absolute % must be 
>10%) 
• 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas 
• 
Development of hypercalcemia (corrected serum calcium 
>11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder 
Source:. Rajkumar, et al. Blood 2011;117(18):4691-5. 
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution 
of any new therapy; complete response and PR and SD categories also require no known evidence of progressive or new bone 
lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether 
disease at Baseline was measurable on serum, urine, both, or neither. Radiographic studies are not required to satisfy these 
response requirements. Bone marrow assessments need not be confirmed. For progressive disease, serum M-component 
increases of ≥1 g/dL are sufficient to define relapse if starting M-component is ≥5 g/dL. 
1 Note clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum 
FLC levels: CR in such patients a normal FLC ratio of 0.26-1.65 in addition to CR criteria listed above. VGPR in such patients 
requires in addition a >90% decrease in the difference between involved and uninvolved free light chain FLC levels. 
2 Note clarifications to IMWG criteria for coding PD: Clarified than bone marrow criteria for progressive disease are to be used 
only in patients without measurable disease by M protein and by FLC levels. Clarified that “25% increase” refers to M protein, 
FLC, and bone marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia. Note that the 
“lowest response value” does not need to be a confirmed value. 
The Investigator’s assessment of disease response will be used for patient management during the study. 
Confirmation of responses should be obtained for biochemical markers but is not necessary for bone 
marrow or imaging studies. The confirmatory tests should be performed by Day 130+/-7 days. The 
response date is not the date of confirmation but the initial date when the assessment met the end point. In 
other words, the second test is confirmatory. If the result is not confirmed by a second evaluation, the 
status is either non-evaluable and the prior disease status remains valid.   
9.3.6. 
Independent Review Committee 
An Independent Review Committee (IRC) will be established under the direction of the Sponsor 
to provide an objective, unbiased, independent review of objective response, using the IMWG 
criteria (Table 6), as demonstrated based on the pertinent clinical data from the study. 
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A formal, written IRC charter will be established outlining the composition of the IRC, the data 
to be evaluated, and the manner of committee meetings.  
9.4. 
Pharmacokinetics 
Serial blood samples for PK analysis will be collected after each tinostamustine dose according 
to the schedule in Table 1. Blood samples for PK assessment should be collected following the 
15-minute supine, resting periods described for the continuous Holter recordings. PK samples are 
to be collected from the arm opposite of that used for tinostamustine administration. 
The calendar date and exact 24-hour clock time of blood sample collection for PK assessments 
will be documented in the source document and the eCRF. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.  
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10. 
STATISTICAL ANALYSES 
10.1. 
Statistical Basis for Sample Size 
Across both Phases 1 and 2 of the study, a total of up to ~86 patients may be enrolled. 
A formal sample size determination/power calculation was not performed for the first phase of 
the study. Based on experience from previously published similar studies, a total number of 
9 (minimum) to 15 (maximum) patients in the dose escalation stage of the study are foreseen. 
For Phase 2 of the study, superiority testing will be performed to investigate the null hypothesis 
that the primary endpoint of responder rate is below or equal to the gold standard against the 
alternative hypothesis that it is higher than the gold standard. The gold standard is assumed to be 
77.5% and a one-sided chi-square test will be performed at the 2.5% level of significance. For 
power considerations, the alternative working hypothesis is that the responder rate for the study 
treatment is at least 90%. 
In the methodology proposed by Simon (Simon, 1989), a Phase 2 design can be represented by 
4 numbers: N1, R1, N, and R. N1 is the sample size in the first stage. R1 is the critical value in 
the first stage. If R1 or fewer responses occur in the N1 patients, the study treatment is rejected. 
N is the combined sample size for both the first and second stages. R is the critical value in the 
combined sample. If R or fewer of the N patients respond, the study treatment is rejected at the 
end. 
The design is found with PASS Sample Size Software through an exhaustive search of all 
possible designs (combinations of R1, N1, R and N) that control alpha (0.025) and beta (0.20, 
meaning power is 0.80). With the minimax approach, the design is selected that has the lowest N. 
Per the minimax design, 31 patients are to be enrolled in Stage 1. If >25 of 31 patients (in the 
FAS) in Stage 1 experience a response to treatment, then enrollment will continue into Stage 2, 
with up to 40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a 
response to treatment, no further patients will be enrolled (in the ongoing Stage 2 recruitment). 
Thus, a total of up to 71 patients will be enrolled in Phase 2.  
If the total number of patients who experience a response is ≥62 of 71, then the study is 
considered a success. 
10.2. 
Statistical and Analytical Plan 
An overview of the statistical methodology to be employed is provided in the following 
subsections. Details regarding the statistical methodology will be documented in a formal 
Statistical Analysis Plan (SAP) prior to database lock.  
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10.2.1. 
General Methods 
Statistical analyses will be primarily descriptive in nature. Statistical hypothesis testing is neither 
intended nor appropriate within this context except for the primary endpoint. Confidence 
intervals will be based on asymptotic methods. 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Categorical variables will be summarized showing 
the number and percentage (n, %) of patients within each classification. 
Dependent of the specific analysis, the analysis sets as defined in Section 10.2.2 will be taken 
from the cohort for Phase 1, for Phase 2 (RP2D) or both phases pooled. Unless specified 
otherwise below, this will be further defined in the SAP. 
10.2.2. 
Analysis Populations 
All patients who receive tinostamustine will be included in the safety set.  
All patients in the safety set who had at least one post-ASCT response evaluation will be 
included in the full analysis set (FAS). 
All patients in the FAS with no major protocol deviations will be included in the per-protocol 
(PP) set. 
All patients in the safety set with at least one quantifiable pre-dose and one quantifiable post-
dose PK plasma concentration will be included in the PK set.  
10.2.3. 
Missing Data 
Analyses will be based on observed data only; no data will be imputed. 
10.2.4. 
Disposition of Patients 
Patients who are screened for study entry and do not meet the eligibility criteria will be 
documented. The numbers and proportions of patients who complete the study and who are early 
terminations will be summarized. Reasons for study discontinuation after the start of study 
treatment will be tabulated. 
10.2.5. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized. Data to be tabulated 
will include demographic and baseline characteristics such as sex, age, race, height, weight, and 
body mass index, and MM-specific diagnostic and historical information. Medical history will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA) and raw and coded data 
will be summarized. 
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10.2.6. 
Extent of Exposure 
Descriptive statistics for the percent of expected dose received and the actual dose received will 
be summarized. A tabular summary and listing of drug administration and dose level, and a by-
patient listing of the date and time of each study drug dose and the dose administered also will be 
presented.  
10.2.7. 
Prior and Concomitant Medications 
Tabulations of prior and concomitant medications, coded using the World Health Organization 
Drug Dictionary (WHO-DD), will be produced. All prior and concomitant medications 
administered will be presented in a data listing.  
10.2.8. 
Efficacy Analyses 
Superiority testing will be performed on FAS in the Phase 2 cohort to investigate the null 
hypothesis that the primary endpoint of responder rate is below or equal to the gold standard 
against the alternative hypothesis that it is higher than the gold standard. The gold standard is 
assumed to be 77.5% (CIBMTR report, December 2017) and a 1-sided 2-step chi-square test will 
be performed at the 2.5% level of significance for FAS. 
For the primary endpoint, also an upper 1-sided 97.5% confidence interval will be calculated for 
FAS in addition to summary statistics. 
For the primary endpoint in other sets and for the secondary endpoints of other responder rates in 
the FAS, also 2-sided 95% confidence intervals will be calculated in addition to summary 
statistics.  
Response assessments as determined by the Investigator and IRC will be compared, with 
agreement determined by Kappa coefficient. 
Disease assessment variables and their changes from baseline will be summarized visit wise.   
10.2.9. 
Pharmacokinetic Analyses 
PK analysis for tinostamustine and its metabolites will be performed using the PK set.  
PK parameters at all doses will include Cmax, time to maximum plasma concentration (tmax), t1/2, 
area under the plasma concentration curve from 0 to 12 hours (AUC0-12), area under the plasma 
concentration curve from time 0 to time t (AUC0-t), apparent total clearance (CL/F), apparent 
volume of distribution (Vd/F), and terminal disposition rate constant (λz). The initial calculation 
of PK parameters will be performed using non-compartmental analysis. Plasma concentrations 
and PK parameters will be summarized by dose. 
Summaries will include the number of observations (n), arithmetic or geometric mean, SD or 
coefficient of variation (CoV), median, minimum, and maximum. 
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10.2.10. 
Safety Analyses 
Safety data, including changes from baseline, if applicable, will be summarized at each dose 
level for the safety set. 
Adverse Events will be coded using MedDRA and raw and coded data will be summarized. 
Additional safety analyses may be determined at any time without prejudice, in order to 
enumerate rates of toxicities most clearly, and to define further the safety profile of 
tinostamustine. 
10.2.11. 
Interim Analyses 
In Phase 2 of the study, at the completion of the Stage 1 with 31 patients, an interim analysis will 
be performed using the FAS for the Phase 2 cohort to determine whether enrollment will 
continue in Stage 2. If >25 of 31 patients in Stage 1 experience a response to treatment, then 
enrollment will continue in Stage 2, with up to 40 patients planned to be enrolled. However, if 
≤25 patients in Stage 1 experience a response to treatment, no further patients will be enrolled in 
in the ongoing Stage 2 recruitment.   
10.3. 
Changes to the Planned Statistical Methods 
Changes to the planned statistical methods will be documented in the clinical study report. 
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11. 
ETHICAL, LEGAL, AND ADMINISTRATIVE 
CONSIDERATIONS 
11.1. 
Good Clinical Practice 
This study will be conducted according to the protocol and in compliance with ICH GCP, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory 
requirements. 
The Investigator confirms this by signing the protocol. 
11.2. 
Informed Consent  
Written informed consent will be obtained from each patient prior to undergoing any protocol-
specific tests or procedures that are not part of routine care. 
The Sponsor or designee will provide an ICF template to the Investigator for use in developing a 
study center-specific consent documents. Prior to submission of the study center-specific ICF to 
the IRB/EC, these documents must be reviewed and approved by the Sponsor or designee. Any 
changes requested by the IRB/EC must also be approved by the Sponsor or designee. The final 
IRB/EC-approved ICF must be provided to the Sponsor or designee. Revisions to the ICF 
required during the study must be approved by the Sponsor r designee, and a copy of the revised 
ICF provided to the Sponsor or designee. 
Before recruitment and enrollment, each prospective patient will be given a full explanation of 
the study and be allowed to read the ICF in a language they understand. After the Investigator or 
designee is assured that the patient understands the commitments of participating in the study, 
the patient will be asked to sign and date the ICF, as appropriate.  
A copy of the fully signed and dated ICF will be given to the patient. The original will be 
maintained in the patient’s medical record at the study center. All active patients will sign an 
updated ICF if revisions are made to the ICF during the course of the study. 
11.3. 
Institutional Review Board/Ethics Committee 
Federal and European regulations and ICH require that approval be obtained from an IRB/EC 
prior to participation of patients in research studies. Approval by the Competent Authority, if 
applicable, or as required by local laws and regulations, is also required in Europe. Prior to the 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian, must be approved by the IRB/EC. 
All IRB/EC approvals must be dated and signed by the IRB/EC Chairperson or designee and 
must identify the IRB/EC 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. 
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No drug will be released to the site to dose a patient until written IRB/EC 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/EC. The Investigator must supply the Sponsor or 
designee with written documentation of the approval of the continued clinical research. 
The Investigator, sponsor, or designee as applicable, will make all attempts to ensure that the 
IRB/EC is constituted and operates in accordance with Federal and ICH GCP and any local 
regulations. 
11.4. 
Amending the Protocol 
Any changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor or designee and the IRB/EC that 
approved the study. Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB/EC for approval prior to patients being enrolled into the amended protocol. 
The Sponsor may make administrative changes (i.e., changes that do not significantly affect 
patient safety or the study’s scope or scientific quality) without any further approvals.  
All amendments will be distributed to all protocol recipients. 
11.5. 
Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and other 
study personnel must not disclose such information without prior written approval from the 
Sponsor. 
Patient confidentiality will be strictly maintained to the extent possible under the law. Patient 
names must not be disclosed. Patients will be identified in the eCRFs and other documents 
submitted to the Sponsor or its designated representative, by their initials, birth date, and/or 
assigned patient number. Documents that identify the patient (e.g., the signed ICF) should not to 
be submitted to the Sponsor or its designated representative, and must be maintained in 
confidence by the Investigator. 
11.6. 
Publication Policy 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. The initial planned publication will be 
a multicenter report of the study outcome. Additional publications from a given center can only 
occur after the publication of the multicenter results. A prepublication manuscript is to be 
provided to the Sponsor at least 30 days prior to the submission of the manuscript to a publisher. 
Similarly, the Sponsor will provide any company-prepared manuscript to the Investigators for 
review at least 30 days prior to submission to a publisher.  
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12. 
STUDY MANAGEMENT 
12.1. 
Data Quality Assurance 
The Sponsor or its designated representative will conduct a study center visit to verify the 
qualifications of each investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
12.2. 
Case Report Forms and Source Documentation 
The Investigator and designees agree to maintain accurate eCRFs and source documentation as 
part of case histories. Source documents are the originals of any documents used by the 
Investigator or subinvestigator or hospital/institution that allow verification of the existence of 
the patient and substantiate the integrity of the data collected during the study. 
The Sponsor or designee will provide eCRFs to the study center. eCRFs will be completed for 
each patient. It is the Investigator’s responsibility to ensure the accuracy, completeness, and 
timeliness of the data reported in the patient’s eCRF. Source documentation supporting the eCRF 
data should indicate the patient’s participation in the study and should document the dates and 
details of informed consent, study procedures, AEs, and patient status.  
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected/data are available, preferably on the same day that a patient is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data.  
12.3. 
Monitoring 
A CRA, or other representative of the Sponsor, will conduct a study center visit to verify the 
qualifications of each Investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation.  
During the course of the study, the CRA will make study center visits to review protocol 
compliance, compare eCRFs and individual patients’ medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements in respect to GCP. eCRFs will be verified with source documentation. The review 
of medical records will be performed in a manner to ensure that patient confidentiality is 
maintained. 
12.4. 
Inspections 
Regulatory authorities and/or quality assurance personnel from the Sponsor or its designated 
representative, may wish to carry out such source data checks and/or in-center audit inspections. 
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The Investigator assures the Sponsor of the necessary support at all times. In the event of an 
audit, the Investigator agrees to allow the sponsor’s representatives and any regulatory agencies 
access to all study records.  
12.5. 
Financial Disclosure Reporting Obligations 
Investigators and subinvestigators are required to provide financial disclosure information to the 
sponsor to permit the sponsor to fulfill its regulatory obligation. Investigators and 
subinvestigators must commit to promptly updating the information if any relevant changes 
occur during the study and for a period of 1 year after the completion of the study. 
12.6. 
Archiving Study Records 
Essential documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. However, these documents should be 
retained for a longer period if required by the applicable local requirements. 
ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
 
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13. 
REFERENCES 
Ahn C. An evaluation of phase I cancer clinical trial designs. Stat Med 1998;17(14):1537-49. 
Barba P, Piñana JL, Martino R, Valcárcel D, Amorós A, Sureda A, et al. Comparison of two 
pretransplant predictive models and a flexible HCT-CI using different cut points to determine 
low-, intermediate-, and high- risk groups: the flexible HCT-CI is the best predictor of NRM and 
OS in a population of patients undergoing allo-RIC. Biol Blood Marrow Transplant 
2010;16:413-420.  
Batlle M, Morgades M, Vives S, Ferrà C, Oriol A, Sancho JM, et al. Usefulness and safety of 
oral cryotherapy in the prevention of oral mucositis after conditioning regimens with high-dose 
melphalan for autologous stem cell transplantation for lymphoma and myeloma. Eur J Haematol. 
2014;93(6):487-91. 
Bayraktar UD, Bashir Q, Qazilbash M, Champlin RE, Ciurea SO. Fifty years of melphalan use in 
hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013;19(3):344-56.  
Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, et al. A 
randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for 
patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant 2016;51(1):67-
71. 
Dillman RO, Koziol JA. Phase I cancer trials: limitations and implications. Mol Biother 
1992;4(3):117-21. 
Farina L, Bruno B, Patriarca F, Spina F, Sorasio R, Morelli M, et al. The hematopoietic cell 
transplantation comorbidity index (HCT-CI) predicts clinical outcomes in lymphoma and 
myeloma patients after reduced- intensity or non-myeloablative allogeneic stem cell 
transplantation. Leukemia 2009;23:1131-1138.  
Garderet L, D'Souza A, Jacobs P, van Biezen A, Schönland S, Kroeger N, et al. Response 
assessment in myeloma: practical manual on consistent reporting in an era of dramatic 
therapeutic advances. Biol Blood Marrow Transplant. 2017;23(7):1193-1202.  
Gatsonis C, Greenhouse JB. Bayesian methods for phase I clinical trials. Stat Med 
1992;11(10):1377-89. 
Gonsalves WI, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, et al. Second auto-
SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant 2013;48(4):568-73. 
Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one 
size does not fit all. Blood 2014;124(3):344-353. 
International Council for Harmonisation. E8:  General Considerations of for Clinical Trials, July 
1997. 
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Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J, et al. Autologous stem cell 
transplantation: an effective salvage therapy in multiple myeloma. Biol Blood Marrow 
Transplant 2013 Mar;19(3):445-9. 
Maruyama D, Fukuda T, Kato R, Yamasaki S, Usui E, Morita-Hoshi Y, et al. Comparable 
antileukemia/lymphoma effects in nonremission patients undergoing allogeneic hematopoietic 
cell transplantation with a conventional cytoreductive or reduced- intensity regimen. Blood 
Marrow Transplant 2007;13:932-941.  
Maybury B, Cook G, Pratt G, Yong K, Ramasamy K. Augmenting Autologous Stem Cell 
Transplantation to Improve Outcomes in Myeloma. Biol Blood Marrow Transplant 
2016;22(11):1926-1937.  
McCarthy PL, Hahn T. Strategies for induction, autologous hematopoietic stem cell 
transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma 
patients. Hematology Am Soc Hematol Educ Program 2013;2013:496-503. 
Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI, et al. Salvage second 
hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant 2013;19(5):760-
6.  
Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body 
irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell 
transplantation in patients with newly diagnosed multiple myeloma: final analysis of the 
Intergroupe Francophone du Myélome 9502 randomized trial. Blood 2002;99:731-735 
Musso M, Messina G, Marcacci G, Crescimanno A, Console G, Donnarumma D, et al. High-
Dose melphalan plus thiotepa as conditioning regimen before second autologous stem cell 
transplantation for “de novo” multiple myeloma patients: a phase II study. Biol Blood Marrow 
Transplant 2015;21:1932e1938. 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:  
Multiple Myeloma, Version 3.2018, November 22, 2017. Available 
at:  https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed:  29 
November, 2017. 
Reece D, Song K, LeBlanc R, Mezzi K, Olujohungbe A, White D, et al. Efficacy and safety of 
busulfan-based conditioning regimens for multiple myeloma. Oncologist 2013;18(5):611-8. 
Simon R. Optimal two-stage deigns for phase II clinical trials. Controlled Clinical Trials 
1989;10:1-10. 
Sorror ML, Giralt S, Sandmaier BM, de Lima M, Shahjahan M, Maloney DG, et al. 
Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for 
patients with acute myeloid leukemia in first remission: Combined FHCRC and MDACC 
experiences. Blood 2007;110:4608-4613.  
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Storer BE. Design and analysis of phase I clinical trials. Biometrics 1989;45(3):925-37. 
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Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
2 
Version 2.0 
INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by Mundipharma EDO, or its 
designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Ethics Committee (EC). No changes will be made to the 
study protocol without the prior written approval of Mundipharma EDO and the IRB/EC, 
except where necessary to eliminate an immediate hazard to a patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
Investigator Signature 
Date 
 
Printed Name 
 
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Titanium 1 
Phase 1/2 Trial of Tinostamustine Conditioning and Autologous Stem Cell Transplantation for Treatment 
in Relapsed / Refractory Multiple Myeloma  
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Phase 1/2 Open-label Trial of Tinostamustine Conditioning and Autologous Stem Cell Transplantation 
for Salvage Treatment in Relapsed / Refractory Multiple Myeloma (TITANIUM 1) 
,QYHVWLJDWRUV&HQWUHV Multicenter study; up to 18 centers in the US and Europe will be enrolling 
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Phase 1 
The primary objectives of Phase 1 of this study are to: 
x 
Establish the safety, toxicity, and maximum tolerated dose (MTD) of the tinostamustine 
conditioning regimen.  
x 
Identify the recommended Phase 2 dose (RP2D) of tinostamustine for use in the Phase 2 portion 
of the study. 
The secondary objective of Phase 1 of this study is to: 
x 
Investigate the pharmacokinetics (PK) of tinostamustine. 
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Protocol No. EDO-S101-1004
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Phase 2 
The primary objectives of Phase 2 of the study are to: 
x 
Investigate the efficacy of the tinostamustine conditioning regimen at the RP2D dose. 
x 
Investigate the safety of the tinostamustine conditioning regimen. 
The secondary objective of Phase 2 of this study is to: 
x 
Evaluate the PK of tinostamustine. 
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Efficacy 
The primary efficacy endpoint in Phase 2 of the study is: 
x 
Objective response rate (ORR): complete response [CR], very good partial response [VGPR] and 
partial response [PR]  at Day 100 (±7 days) post-autologous stem cell transplant (ASCT). 
Secondary efficacy endpoints among patients treated at the RP2D (in Phases 1 and 2) are: 
x 
ORR, and, in patients who achieve CR, minimal residual disease-negativity (MRD-N), as 
determined by next-generation flow cytometry at Day 100 (±7 days) post-ASCT. 
Safety 
The safety endpoint in Phase 1 of the study is: 
x 
Dose-limiting toxicities (DLT). 
Additional safety endpoints in Phases 1 and 2 of the study are: 
x 
Incidence of neutrophil and platelet engraftment failure. 
x 
Duration of cytopenia (i.e., absolute neutrophil count [ANC] ≤0.5×109/L, platelet count 
≤20×109/L). 
x 
Cumulative incidence of treatment-related mortality (TRM). 
x 
Transplant-related non-hematologic Grade 3 toxicity over time through Day 30, stratified by 
hematopoietic cell transplantation comorbidity index (HCT-CI). 
x 
Incidence of adverse events (AEs) and serious adverse events (SAEs).
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This is a 2-part, international, multi-center, open-label study of salvage treatment with tinostamustine 
conditioning followed by ASCT in patients with relapsed/ refractory multiple myeloma (MM). (ASCT is 
defined as salvage if the patient had already received a prior ASCT and undergoes a second ASCT after 
evidence of progressive disease [PD].)  
Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of defining the 
DLTs of the tinostamustine conditioning regimen and defining the MTD and RP2D for use in the Phase 2 
portion of the study.  
The initial dose of tinostamustine in the Phase 1 portion of the study is 180 mg/m2, with escalation to 220, 
260, and then 300 mg/m2 (or higher) planned. If the 180 mg/m2 dose level is not tolerable, then a lower 
tinostamustine dose of 160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, with 
<33% of patients experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may be explored. 
The Safety Review Committee can make a decision to stop dose escalation or explore intermediary doses 
at any time. 
The total dose of tinostamustine will be administered on Day -1.  
Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up to 
31 patients initially will be enrolled. If ≤25 patients of these initial 31 patients experience a response, then 
no additional patients will be enrolled. However, if >25 patients in Stage 1 of Phase 2 experience a 
response, then enrollment in this cohort will continue, with up to 71 patients enrolled. In Phase 2 of the 
study, all patients will receive tinostamustine at the RP2D administered in Phase 1 according to the same 
schedule. 
After provision of written informed consent, patients will be screened for study eligibility within 28 days 
before Day 1 (the day of ASCT). Patients who have a minimum of 2×106 CD34+ cells/kg cryopreserved 
and are otherwise determined to be eligible, based on screening assessments, will be enrolled and receive 
the tinostamustine conditioning regimen. The tinostamustine dose will be administered 24 hours pre-
ASCT (i.e., Day -1). 
On Day 1, ASCs will be administered intravenously (IV) according to standard institutional practice.  
Patients will receive supportive measures (including growth factor support post-ASCT, antimicrobial 
prophylaxis, red blood cell and platelet transfusion, and treatment for neutropenic fever) according to 
standard institutional practice. 
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During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 Day 30 (±5 
days) post-ASCT or until all transplant-related toxicity resolves. Patients will be discharged from the 
study center once the following engraftment criteria are met: 
x 
Neutrophil engraftment is defined as the first of 3 consecutive days with ANC >0.5×109/L.  
x 
Platelet engraftment will be defined as the first of 3 consecutive days of platelet count >20×109/L 
without platelet transfusion in the prior 7 days. 
Thereafter, patients will attend study center visits at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
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Toxicity will be assessed by the Investigator using the US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
In Phase 1 of the study, DLT is defined as the occurrence of any of the following events occurring within 
30 days post-ASCT that are considered by the Investigator to be at least possibly related to 
tinostamustine: 
x 
Delayed engraftment (>30 days after ASCT). Engraftment will be considered delayed if the 
subject has not met criteria for both neutrophil and platelet engraftment:  
 Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
 Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days.  
x 
QTcF >500 msec or >60 msec increase from baseline, with a duration of >30 minutes, or 
≥Grade 3 QTcF interval prolongation accompanied by ventricular arrhythmia. Baseline QTcF 
interval will be the mean value determined during triplicate ECG(s) at Day -1 (-1day), before 
study drug administration; the mean QTcF will be confirmed by the cental laboratory.  
x 
Grade 4 non-hematologic toxicity  
x 
Grade 3, non-hematologic toxicity related to treatment, ZLWKWKHH[FHSWLRQRI 
 Nausea or vomiting  
 Diarrhea  
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
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 Fatigue, dehydration, or glucose intolerance 
 Skin rash, dry skin, or pruritus responsive to topical or systemic steroids 
 Fever (>40ºC for ≤24 hours) 
 Infection 
 Dyspnea, hypoxia, or pneumonitis 
 Abdominal pain 
 Dysphagia, oral mucositis, oral pain, or anorexia 
 Flu-like syndrome 
 Engraftment syndrome  
 Weight loss 
 Pain, pain in extremity, headache, or insomnia 
 Hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, or hypophosphatemia 
 Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, 
or alkaline phosphatase 
 Alopecia
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In Phase 1, up to 3 patients initially are to be enrolled in each cohort. The first patient enrolled in the 
initial cohort must complete the study through engraftment without a ≥Grade 3 toxicity or through 
30 days post-ASCT without a DLT, whichever occurs first, before additional patients may be enrolled in 
that initial cohort. (If the first patient experiences a DLT, then a lower dose will be explored for the 
second patient, and so on.) 
x 
If the first patient does not experience a DLT or experiences engraftment without a ≥Grade 3 
toxicity, the next 2 patients may be enrolled simultaneously. 
After 3 patients in a cohort complete the study through engraftment without a ≥Grade 3 toxicity or 
through 30 days post-ASCT without a DLT, whichever occurs first, and have safety evaluations 
performed through that time, and: 
x 
None of these 3 patients experience a DLT, then enrollment of the next cohort may commence 
Mundipharma-EDO GmbH
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Protocol No. EDO-S101-1004
13 May 2020
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with approval from the Safety Committee. 
x 
1 of 3 patients within a cohort experiences a DLT, then up to 3 additional patients are to be 
enrolled sequentially at that dose level. If none of the additional 3 patients has a DLT (i.e., 1 of 
6 patients has a DLT), then enrollment at the next scheduled dose may commence with approval 
from the Safety Committee. 
x 
If t2 patients within a cohort experience a DLT, then the DLT dose level will have been reached 
and the previous lower dose level will be considered the MTD. (If t2 patients in the initial dose 
cohort experience DLTs, then the dose will be reduced to one level lower and the same procedure 
will be followed.) 
A total of 6 patients are planned to be treated at the MTD to confirm the RP2D before enrollment of 
patients in Phase 2 of the study. If the MTD is not confirmed at this stage, the dose will be reduced to one 
level lower and the same procedure will be followed. 
Note that enrollment in the next dose cohort can begin only when the last patient enrolled in the current 
dose cohort completes the study through engraftment without a ≥Grade 3 toxicity or through 30 days 
post-ASCT without a DLT, whichever occurs first, provided that <2 patients in the current dose cohort 
experienced a DLT.  
Although decisions regarding dose escalation will be made based on review of data through Day 30 post-
ASCT, safety data will also be collected from all patients continuing in the study and this will be 
reviewed periodically by the Safety Committee. Any detected toxicity may necessitate further refinement 
of the RP2D.
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The MTD is defined as the highest dose level at which ≤1 of 6 patients experiences DLT through 30 days 
post-ASCT.
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The RP2D may be equal to or higher than the preliminary MTD, but less than the non-tolerated dose (i.e., 
the dose at which ≥2 of 6 patients experienced DLT). The RP2D will be determined in discussion with the 
Sponsor, Medical Monitor, and Investigators. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
89
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Phase 1 
A total of 9-12 patients are planned to be enrolled in Phase 1.  
Phase 2 
A total of up to 71 patients are planned to be enrolled in Phase 2.  
Criteria for Inclusion/Exclusion: 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for enrollment: 
1. Patient has MM and: 
a. Has received prior ASCT after standard first-line induction treatment. 
b. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18 months in 
Phase 2. 
Progression Free Inteval is defined as the time from date of ASCT to PD. 
c. Received treatment with ≤3 prior lines of therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. When 
patients have undergone sequential phases of treatment without intervening progression, such 
as induction, collection of peripheral blood stem cells, transplantation and 
consolidation/maintenance, this is considered to be 1 line of treatment. A new line of therapy 
is initiated as a result of PD or relapse (Garderet et al, 2017). 
2. CR, VGPR, PR, or minimal response (MR) to latest of salvage chemotherapy at relaps, as 
determined by the International Myeloma Working Group (IMWG) criteria.  
3. Is, in the Investigator’s opinion, a candidate for consolidation therapy with tinostamustine 
followed by ASCT. (Note that patients planned to receive tandem ASCT are not eligible for the 
Phase 1 portion of the study.) 
4. Has available autologous peripheral blood stem cell (PBSC) product with CD34 cell dose ≥2×106 
cells/kg. The product could be from a collection prior to first ASCT or later second collection. 
(Note that, although not required, in Phase 1, the Investigator should consider enrolling patient 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
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with a large number of available PBSCs to permit subsequent ASCT, as patients in Stage 1 may 
received a dose lower that that determined to be effective.) 
5. Age 18-75 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score <3 at Screening. 
7. Creatinine clearance ≥40 mL/min, as determined by a local laboratory using the Cockcroft-Gault 
equation within 28 days before ASCT. 
8. Left ventricular ejection fraction (LVEF) ≥40% within 28 days before ASCT. 
9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), forced 
vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) >50% predicted within 28 
days before ASCT.  
10. Adequate liver function, as defined by an ALT and AST ≤2.5 × the upper limit of normal (ULN) 
and bilirubin ≤1.5 × ULN within 28 days before ASCT.  
11. Potassium within the local laboratory’s normal range. (Potassium supplementation is 
permissible.) 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment in the study: 
1. History of central nervous system (CNS) disease involvement. 
2. Myocardial infarction (MI) or stroke within 6 months before Screening.  
3. Uncontrolled acute infection. 
4. HCT-CI >6 points. 
5. Concurrent malignant disease with the exception of treated basalioma/spinalioma of the skin or 
early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment for other 
malignancies (not listed above) must have been terminated at least 24 months before registration 
and no evidence of active disease shall be documented since then. 
6. Major coagulopathy or bleeding disorder. 
7. Other serious medical condition that could potentially interfere with the completion of treatment 
according to this protocol or that would impair tolerance to therapy or prolong hematological 
recovery. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
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8. Lack of cooperation to allow study treatment as outlined in this protocol. 
9. Pregnancy or lactating female patients.  
10. The use of any antiǦ cancer investigational agents within 21 days prior to the expected start of 
trial treatment and interval of 14 days to last administration of salvage treatment. 
11. Receiving treatment with drugs known to prolong the QT/QTc interval. 
12. QTc interval (Fridericia’s formula) >450 msec, based on the mean of triplicate Screening 12-lead 
ECGs. 
7HVW7UHDWPHQW'RVHDQG0RGHRI$GPLQLVWUDWLRQ
Tinostamustine (formerly EDO-S101) 
 
 
 
 
 
 
 The drug 
substance is a class 4 cytotoxic agent and should be handled with care by experienced health care 
professionals. 
For administration, tinostamustine powder is reconstituted with 20 mL saline (0.9%) and then further 
diluted with saline (0.9%) to a final volume of 50 mL.
 
 
In Phase 1 of the study, the starting dose of tinostamustine is 180 mg/m2, with escalation to 220, 260, and 
then 300 mg/m2 or higher planned. If the 180 mg/m2 dose level is not tolerable, then a lower 
tinostamustine dose of 160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, with 
<33% of patients experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may be explored. 
The Safety Review Committee can make a decision to stop dose escalation or explore intermediary doses 
at any time. In Phase 2, patient will receive tinostamustine at the RP2D identified in Phase 1. The total 
tinostamustine dose will be administered on Day -1. Tinostamustine will be administered by IV infusion 
through a peripheral vein over 1 hour.  
Twenty-four hours after the tinostamustine infusion, ASCs will be infused via central venous catheter on 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
92
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Day 1. If the CD34+ product is of large volume, the infusion can be given over 2 days. 
Patients may receive the following supportive care:   
x 
IV hydration and anti-emetics, in accordance with institutional guidelines. 
x 
Growth factor support with pegfilgrastim or equivalent agent post-ASCT, in accordance with 
institutional guidelines.  
x 
Standard supportive care, in accordance with institutional guidelines, including blood product 
transfusions, antimicrobial prophylaxis, and treatment for febrile neutropenia. 
'XUDWLRQRI7UHDWPHQWDQG6WXG\'XUDWLRQ
All patients will receive 1 doses of tinostamustine on Days -1 followed by ASCT on Day 1. 
The anticipated accrual is 9-12 patients/year in Phase 1. Recruitment will continue during the evaluation 
period needed for Stage 1 of Phase 2. All patients will be followed for a maximum of 130 (±7 days) post-
ASCT thus yielding a study of total duration of approximately 2.5 to 3.5 years.  
&ULWHULDIRU(YDOXDWLRQ 
Efficacy Assessment(s):  
Response will be determined by the Investigator using the IMWG criteria. In addition, response of each 
subject will be evaluated by two independent reviewers, otherwise not involved in the clinical trial.  In 
order to assess response, M protein component is to be measured in serum and/or urine, free light chain 
(FLC) testing is to be performed. Note that in the case of immunoglobulin A (IgA) MM, MM IgA values 
should be used. Bone marrow aspirate or biopsy and imaging studies (e.g., computed tomography, 
magnetic resonance imaging) are to be performed as clinically indicated. For patients with CR, based on 
serum and urine analysis, bone marrow aspirate and biopsies are to be performed at Day 100 (±7days), 
including the myeloma immunophenotype.  
Confirmatory assessment: A second assessment of response will be conducted between 107 and 130 to 
confirm the response. If the result is not confirmed by a second evaluation, the status is either Non 
Evaluable (NE) or the prior disease status remains valid. Confirmation should be obtained for 
biochemical markers but ius not necessary for bone marrow or imaging studies, 
Assessment of M protein in serum and urine should be performed any time relapse is suspected. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
93
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Drug Concentration Measurements:  
Serial blood samples for PK analysis will be collected before, duration, and after tinostamustine 
administration according to the schedule in Table 1. Samples will be collected, labelled, stored and 
shipped as detailed in the Laboratory Manual. 
Bioanalytical Methods: 
A fully validated LC-MS/MS method for the determination of EDO-S101 and its metabolites (M2 and 
M8) in human plasma will be utilised. 
 
   
 
Safety Assessments:  
Safety will be assessed by documentation of AEs, safety laboratory tests (hematology and clinical 
chemistries), ECOG performance status, vital signs, physical examinations, electrocardiograms (ECGs), 
and Holter monitoring.  
During in-patient hospitalization, patients will be assessed daily for hematologic engraftment until and 
including the day the patient has an ANC >0.5 ×109/L and platelet count > 20×109/L without transfusion 
support.  
To assess for early renal toxicity, creatinine, urea, and uric acid will be assessed on a daily basis from the 
start of tinostamustine treatment through Day 3 post-ASCT. In case of clinically significant renal toxicity, 
creatinine, urea, and uric acid will be assessed as long as clinically indicated.  
6WDWLVWLFDO0HWKRGV 
Analysis Populations 
All patients who receive tinostamustine will be included in the safety set.  
All patients in the safety set who had at least one post-ASCT response evaluation will be included in the 
full analysis set (FAS). 
All patients in the FAS with no major protocol deviations will be included in the per-protocol (PP) set. 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
94
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All patients in the safety set with at least one quantifiable pre-dose and one quantifiable post-dose PK 
plasma concentration will be included in the PK set.  
Dependent of the specific analysis, these sets will be taken from the cohort for Phase 1, for Phase 2 
(RP2D), or both phases pooled. 
Efficacy Analyses:   
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Summaries for categorical variables 
will include frequency counts and percentages. 
Superiority testing will be performed on FAS in Phase 2 cohort to investigate the null hypothesis that the 
primary endpoint of responder rate is below or equal to the gold standard against the alternative 
hypothesis that it is higher than the gold standard. The gold standard is assumed to be 77.5% (CIBMTR 
report, December 2017) and a 1-sided, 2-step chi-square test will be performed at the 2.5% level of 
significance for FAS.  
For the primary endpoint, also an upper 1-sided 97.5% confidence interval will be calculated for FAS in 
addition to summary statistics. 
For the primary endpoint in other sets and for the secondary endpoints of other responder rates in the 
FAS, also 2-sided 95% confidence intervals will be calculated in addition to summary statistics. 
Interim Analyses: 
In Phase 2 of the study, at the completion of the Stage 1 with 31 patients, an interim analysis will be 
performed using the FAS for the Phase 2 cohort to determine whether enrollment will continue in Stage 2. 
If >25 of 31 patients in Stage 1 experience a response to treatment, then enrollment will continue into 
Stage 2, with up to 40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a 
response to treatment, no further patients will be enrolled (in the ongoing Stage 2 recruitment).   
Pharmacokinetic Analyses:  
PK analysis for tinostamustine and its metabolites will be performed using the PK set.  
PK parameters at all doses will include maximum plasma concentration (Cmax), time to maximum plasma 
concentration (tmax), half-life (t½) area under the plasma concentration curve from 0 to 12 hours (AUC0-12), 
area under the plasma concentration curve from time 0 to time t (AUC0-t), apparent total clearance (CL/F), 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
95
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apparent volume of distribution (Vd/F), and terminal disposition rate constant (λz). The initial calculation 
of PK parameters will be performed using non-compartmental analysis. Plasma concentrations and PK 
parameters will be summarized by dose. 
Summaries will include the number of observations (n), arithmetic or geometric mean, SD or coefficient 
of variation (CoV), median, minimum, and maximum. 
Safety Analyses: 
Safety data, including changes from baseline if applicable will be summarized at each dose level for the 
safety set. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Summaries for categorical variables will include frequency 
counts and percentages. 
6DPSOH6L]H5DWLRQDOH 
Across both Phases 1 and 2 of the study, a total of up to ~86 patients may be enrolled. 
For Phase 1, a formal sample size determination/power calculation was not performed. Based on 
experience from previously published similar studies, a total number of 9 (minimum) to 12 (maximum) 
patients in the dose escalation stage of the study are foreseen. 
For Phase 2 of the study, superiority testing will be performed to investigate the null hypothesis that the 
primary endpoint of responder rate is below or equal to the gold standard against the alternative 
hypothesis that it is higher than the gold standard. The gold standard is assumed to be 77.5% (CIBMTR 
report, December 2017) and a one-sided chi-square test will be performed at the 2.5% level of 
significance. For power considerations, the alternative working hypothesis is that the responder rate for 
the study drug is at least 90%. 
In the methodology proposed by Simon (Simon, 1989), a Phase 2 design can be represented by 
4 numbers: N1, R1, N, and R. N1 is the sample size in the first stage. R1 is the critical value in the first 
stage. If R1 or fewer responses occur in the N1 patients, the study treatment is rejected. N is the combined 
sample size for both the first and second stages. R is the critical value in the combined sample. If R or 
fewer of the N patients respond, the study treatment is rejected at the end. 
The design is found with PASS Sample Size Software through an exhaustive search of all possible 
designs (combinations of R1, N1, R and N) that control alpha (0.025) and beta (0.20, meaning power is 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
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0.80). With the minimax approach, the design is selected that has the lowest N. 
Per the minimax design, 31 patients are to be enrolled in Stage 1. If >25 of 31 patients (in the FAS) in 
Stage 1 experience a response to treatment, then enrollment will continue in Stage 2, with up to 
40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a response to treatment, 
no further patients will be enrolled. Thus, a total of up to 71 patients will be enrolled in Phase 2.  
If the total number of patients who experience a response is ≥62 of 71, then the study is considered a 
success. 
6FKHGXOHRI(YHQWV
The schedule of events is presented in Table 1. 
 

Mundipharma-EDO GmbH
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Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
17 
Version 2.0 
Table 1: 
Schedule of Events (Phases 1 and 2) 
Procedure 
Screening 
Conditioning 
ASCT 
Post-ASCT Follow-up1 
D-28 to -1 
D-1 
D0 
M1 
M2 
D100 
(±7 days) 
D130 
(±7 days) 
Written informed consent2 
X 
 
 
 
 
 
 
Eligibility review 
X 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
HCT-CI 
X 
 
 
 
 
 
 
Cancer history, including history of prior ASCT and 
other treatments 
X 
 
 
 
 
 
 
ECHO or MUGA scan 
X 
 
 
 
 
 
 
Pulmonary function testing3 
X 
 
 
 
 
 
 
Infectious disease screening4 
X 
 
 
 
 
 
 
Pregnancy test5 
X 
 
 
 
 
 
 
ECOG performance status 
X 
 
X 
X 
X 
X 
 
Complete physical examination 
X 
 
 
 
 
 
 
Targeted physical examination 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
 
Vital signs6 
X 
X 
X7 
X 
X 
X 
 
Continuous Holter monitoring 
 
X9 
 
 
 
 
 
12-lead ECG10 
X11 
X11 
 
X 
 
 
 
Hematology12 
X 
Repeat daily until hospital discharge 
 
 
 
Kidney function tests (creatinine, urea, and uric acid) 
 
Daily from the start of 
tinostamustine through Day 3post-
ASCT 
 
 
 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
98


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
18 
Version 2.0 
Procedure 
Screening 
Conditioning 
ASCT 
Post-ASCT Follow-up1 
D-28 to -1 
D-1 
D0 
M1 
M2 
D100 
(±7 days) 
D130 
(±7 days) 
Clinical chemistries13 
X 
X 
X 
X 
X 
X 
 
Coagulation parameters: PT and/or INR, aPTT 
X 
 
X 
X 
 
X 
 
Urinalysis14 
X 
 
 
 
 
 
 
Tinostamustine administration15 
 
X 
 
 
 
 
 
PK sample collection 
 
X16 
 
 
 
 
 
ASCT17 
 
 
X 
 
 
 
 
Disease assessments 
 
 
 
 
 
 
 
Skeletal survey18 
X 
 
 
 
 
 
 
Bone marrow aspirate and biopsy19 
X 
 
 
 
 
D100 
(±7 days)20 
 
Serum / urine M protein quantitation 
X 
 
 
X 
X 
X 
X 
Immunoglobulin quantitation 
(IgA, IgG, and IgM [required]; IgD, IgE [optional]) 
X 
 
 
X 
X 
X 
X 
Free light chain analysis 
X 
 
 
X 
X 
X 
X 
Disease response assessment21 
X 
 
 
X 
X 
X 
 
Evaluation for MRD-N 
 
 
 
 
 
D100 
(±7 days)20 
 
AE monitoring22 
AEs, including SAEs, are to be documented from the provision of written informed consent through Day 100. 
 
Prior/concomitant medications23 
All medications administered within 28 days before Day 1 through Day 100 are to be documented. 
 
1. 
Patients will be evaluated daily on an inpatient basis until engraftment criteria are met and the patient is discharged from the hospital. Thereafter, study center visits will be 
performed on an outpatient basis. Visit M1: D30  ( ±5days); visit M2: D60  (±5days)  
2. 
Written informed consent is to be obtained before the performance of any study-related procedures. 
3. 
Pulmonary function testing is to include FEV1, FVC, and DLCO. 
4. 
Infectious disease marker testing is to include, at a minimum, human immunodeficiency virus (HIV) types 1 and 2, hepatitis B virus (HBV) panel (HBV surface antigen, 
HBV surface antibody, HBV core antibody, HBV e-antigen), hepatitis C virus (HCV), Treponema pallidum, CMV, and Epstein-Barr virus. 
5. 
Urine or serum pregnancy testing will be performed for women of childbearing potential. Pregnancy testing is to be repeated on study any time pregnancy is suspected. 
6. 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital signs are to be measured after patient is sitting for 3-5 minutes.  
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
99


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
19 
Version 2.0 
7. 
Perform assessment both pre- and post-treatment. 
8. 
ECGs (12-lead) are to be performed after the patient is supine for 5 minutes. Repeat ECGs as clinically indicated. Screening ECGs will be reviewd centrally. Regarding other  
12 lead ECGs: the investigator or the sponsor may request expedited central review of ECGs, as clinically indicated. 
9. 
Continuous Holter monitoring will be performed on Day -1, the day of tinostamustine administration. Holter monitoring will commence 15 minutes prior to the start of the 
infusion on Day -1 and will continue through 24 hours following the end of infusion. Patients should be resting comfortably in the supine or semisupine position for 15 
minutes prior to each of the following timepoints: 0 [before start of infusion] then after start of the infusion at 15, 30, 45, and 60 minutes and 3, 6, and 24 hours following the 
start of the infusion. At time 0 and at all time points after infusion, ECGs readings will be extracted in triplicate, with each ECG separated by 5 minutes (±2 minutes), for 
establishment of baseline for the purposes of cardiac safety analyses. The Holter monitor flashcards will be sent to eResearch Technology, Inc., for processing.  
10. 
The Investigator’s interpretation of ECGs is to be used for patient management during the study; the central reader interpretation of ECGs extracted from Holter monitoring 
will be used to determine all ECG data for study endpoints including baseline QTcF interval for cardiac safety analyses and DLTs. 
11. 
A triplicate ECG will be performed during Screening to determine patient eligibility for the study. Furthermore, on Day -1, a triplicate ECG is to be performed before study 
drug administration and a single ECGs will be performed at 30 and 60 minutes after the start of study drug administration for assessment by the site. Another single ECG will 
be performed at visit on day 30 (±5 days). ECGs are to be repeated by the Investigator, as clinically indicated. 
12. 
Hematology parameters minimally include WBC count and differential (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) count, 
hematocrit, hemoglobin, and platelet count. 
13. 
Serum chemistry parameters minimally include alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase, (AST), bicarbonate, 
bilirubin (total, direct, and indirect), calcium, magnesium, chloride, glucose, lactate dehydrogenase (LDH), phosphate, potassium, sodium, and total protein. 
14. 
Urinalysis includes appearance, color, pH, specific gravity, ketones, leukocytes, protein, glucose, bilirubin, urobilinogen, and occult blood. 
15. 
The tinostamustine dose will be administered one day before ASCT (Day -1), at least 24 hours pre-ASCT.  
16. 
Blood samples for PK are to be collected immediately pre-infusion of tinostamustine and 30, 45, and 60 (±5) minutes and then at 3, 6, and 24 hours (±15 minutes) and then 
48 hours (±30 minutes) after the start of infusion. Blood samples for PK assessment should be collected following the 15-minute supine resting periods described for the 
continuous Holter recordings. PK samples are to be collected from the arm opposite of that used for tinostamustine administration. 
17. 
On Day 1, ASCs will be administered IV according to standard institutional practice. If the CD34+ product is of large volume, the infusion can be given over 2 days. 
18. 
A skeletal survey (plain radiographs, or any other method used as standard care at the site, of the skull, spine, ribs, pelvis, humeri and femora) will be performed at Screening 
if not performed within the previous 3 months. Thereafter, skeletal survey and/or other imaging studies are to be performed as clinically indicated. 
19. 
Bone marrow aspirate and trephine biopsy are to be performed during Screening. Bone marrow aspirate and biopsy are to be repeated during treatment as clinically indicated, 
at the Investigator’s discretion, and at any time CR is suspected.  
20. 
Any patient who achieves a CR will have peripheral blood and bone marrow collected at Day 100 (±7 days) for assessment of evidence of MRD-N via next-generation flow 
cytometry.  
21. 
Disease response will be assessed by the Investigator using the IMWG Criteria. Confirmation should be obtained for biochemical markers but is not necessary for bone 
marrow or imaging studies. There is no specific time interval required between the 2 evaluations, the the confirmatory tests ideally should be performed approximately 
4 weeks after the initial evaluation. 
22. 
AEs will be documented as occurring pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start of the first tinostamustine infusion through 
immediately before the start of autologous stem cell [ASC] infusion); or after ASCT (i.e., after the start of ASC infusion).  
23. 
Concomitant medications will be documented as administered pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start of the first tinostamustine 
infusion through immediately before the start of ASC infusion); or after ASCT (i.e., after the start of ASC infusion). 
 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
100


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
20 
Version 2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AK-DACi 
Alkylating deacetylase inhibitor 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASC 
Autologous stem cell 
ASCT 
Autologous stem cell transplantation 
AST 
Aspartate aminotransferase 
AUC0 12 
Area under the plasma concentration curve from 0 to 12 hours 
AUC0-t 
Area under the plasma concentration curve from time 0 to time t 
CA 
Competent Authorities 
CL/F 
Apparent total clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CoV 
Coefficient of variation 
CR 
Complete response 
CRA 
Clinical Research Associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DLCO 
Carbon monoxide diffusing capacity 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
101


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
21 
Version 2.0 
Abbreviation 
Definition 
EDTA 
Ethylenediaminetetraacetic acid 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FLC 
Free light chain 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 
HCT-CI 
Hematopoietic cell transplantation comorbidity index 
HCV 
Hepatitis C virus 
HDACi 
Histone-deacetylase inhibitor 
HIV 
Human immunodeficiency virus 
HPβCD 
Hydroxyl-propyl-β-cyclodextrin 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
Ig 
Immunoglobulin 
IMWG 
International Myeloma Working Group 
IRB 
Institutional review board 
IRC 
Independent Review Committee 
IV 
Intravenous(ly) 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferase 
MI 
Myocardial infarction 
MM 
Multiple myeloma 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
102


Mundipharma-EDO GmbH 
Clinical Study Protocol EDO-S101-1004 
Version 2.0, 18 June 2018 
 
CONFIDENTIAL 
22 
Version 2.0 
Abbreviation 
Definition 
MR 
Minimal response 
MRD-N 
Minimal residual disease-negativity 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
PBSC 
Peripheral blood stem cell 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PR 
Partial response 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SD 
Standard deviation 
SUSAR 
Serious and unexpected suspected adverse reaction 
t1/2 
half-life 
tmax 
Time to maximum plasma concentration 
TRM 
Treatment-related mortality 
ULN 
Upper limit of normal 
US 
United States 
Vd/F 
Apparent volume of distribution  
VGPR 
Very good partial response 
WHO-DD 
World Health Organisation Drug Dictionary 
λz 
Terminal disposition rate constant 
Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
103


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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
104
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7.5.1.
Dose Escalation Procedure ................................................................... 46
7.5.2.
Definition of Dose-limiting Toxicity .................................................... 47
7.5.3.
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7.5.4.
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7.6.2.
Study Drug Administration ................................................................... 49


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9.1.1.
Informed Consent ................................................................................. 54
9.1.2.
Demographics ....................................................................................... 54
9.1.3.
Medical History, Including Cancer History .......................................... 54
9.1.4.
Hematopoietic Cell Transplantation-Comorbidity Index 
(HCT-CI) .............................................................................................. 54
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9.1.5. 
Prior and Concomitant Medications ..................................................... 54 
9.1.6. 
Echocardiogram or Multi-gated Acquisition Scan ............................... 54 
9.1.7. 
Pulmonary Function Testing ................................................................. 55 
9.1.8. 
Screening Serologies............................................................................. 55 
9.1.9. 
Pregnancy Testing................................................................................. 55 
9.2. 
Safety Measurements ......................................................................................... 55 
9.2.1. 
Physical Examination, .......................................................................... 55 
9.2.2. 
Height and Weight ................................................................................ 56 
9.2.3. 
ECOG Performance Status ................................................................... 56 
9.2.4. 
Vital Signs............................................................................................. 57 
9.2.5. 
Holter Monitoring ................................................................................. 58 
9.2.6. 
12-Lead Electrocardiogram .................................................................. 58 
9.2.7. 
Safety Laboratory Tests ........................................................................ 59 
9.2.8. 
Adverse Events ..................................................................................... 60 
9.3. 
Disease Assessments ........................................................................................... 65 
9.3.1. 
Myeloma Protein Measurements in Serum and Urine .......................... 65 
9.3.2. 
Free Light Chain Testing ...................................................................... 66 
9.3.3. 
Bone Marrow Examination ................................................................... 66 
9.3.4. 
Skeletal Survey and Other Imaging Studies ......................................... 66 
9.3.5. 
Assessment of Disease Response ......................................................... 66 
9.3.6. 
Independent Review Committee ........................................................... 68 
9.4. 
Pharmacokinetics ............................................................................................... 69 
10. 
Statistical Analyses......................................................................................................... 70 
10.1. Statistical Basis for Sample Size ....................................................................... 70 
10.2. Statistical and Analytical Plan .......................................................................... 70 
10.2.1. 
General Methods ................................................................................... 71 
10.2.2. 
Analysis Populations............................................................................. 71 
10.2.3. 
Missing Data ......................................................................................... 71 
10.2.4. 
Disposition of Patients .......................................................................... 71 
10.2.5. 
Demographics and Baseline Characteristics ......................................... 71 
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10.2.6. 
Extent of Exposure................................................................................ 72 
10.2.7. 
Prior and Concomitant Medications ..................................................... 72 
10.2.8. 
Efficacy Analyses ................................................................................. 72 
10.2.9. 
Pharmacokinetic Analyses .................................................................... 72 
10.2.10. Safety Analyses..................................................................................... 73 
10.2.11. Interim Analyses ................................................................................... 73 
10.3. Changes to the Planned Statistical Methods ................................................... 73 
11. 
Ethical, Legal, and Administrative Considerations .................................................... 74 
11.1. Good Clinical Practice ....................................................................................... 74 
11.2. Informed Consent .............................................................................................. 74 
11.3. Institutional Review Board/Ethics Committee ................................................ 74 
11.4. Amending the Protocol ...................................................................................... 75 
11.5. Confidentiality .................................................................................................... 75 
11.6. Publication Policy............................................................................................... 75 
12. 
Study Management ........................................................................................................ 76 
12.1. Data Quality Assurance ..................................................................................... 76 
12.2. Case Report Forms and Source Documentation ............................................. 76 
12.3. Monitoring .......................................................................................................... 76 
12.4. Inspections .......................................................................................................... 76 
12.5. Financial Disclosure Reporting Obligations .................................................... 77 
12.6. Archiving Study Records .................................................................................. 77 
13. 
REFERENCES ............................................................................................................... 78 
 
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LIST OF TABLES IN THE TEXT 
Table 1: 
Schedule of Events (Phases 1 and 2) ................................................................... 17 
Table 2: 
Response Outcomes After ASCT Preceded by Melphalan 
Conditioning (CIBMTR SC17-05 Report) .......................................................... 32 
Table 3: 
Pooled Response Outcomes After ASCT Preceded by Melphalan 
Conditioning ........................................................................................................ 32 
Table 4: 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores .............................................. 57 
Table 5: 
Criteria for Determination of Adverse Event Relationship to Study 
Drug ..................................................................................................................... 62 
Table 6: 
IMWG Response Criteria .................................................................................... 66 
 
 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Phase 1 
3.1.1.1. 
Primary Objectives 
The primary objectives of Phase 1 of this study are to: 
x Establish the safety, toxicity, and MTD of the tinostamustine conditioning regimen.  
x Identify the RP2D of tinostamustine for use in the Phase 2 portion of the study. 
3.1.1.2. 
Secondary Objectives 
The secondary objective of Phase 1 of this study is to: 
x Investigate the PK of tinostamustine. 
3.1.2. 
Phase 2 
3.1.2.1. 
Primary Objectives 
The primary objectives of Phase 2 of the study are to: 
x Investigate the efficacy of the tinostamustine conditioning regimen at the RP2D. 
x Investigate the safety of the tinostamustine conditioning regimen. 
3.1.2.2. 
Secondary Objectives 
The secondary objective of Phase 2 of this study is to: 
x Evaluate the PK of tinostamustine. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy 
3.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint in Phase 2 of the study is: 
x Objective response rate (ORR): complete response [CR] plus partial response [PR] at 
Day 100 (±7 days) post-ASCT. 
3.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints among patients treated at the RP2D (in Phases 1 and 2) are: 
x ORR and, in patients who achieve CR, minimal residual disease-negativity (MRD-N), as 
determined by next-generation flow cytometry at Day 100 (±7 days) post-ASCT. 
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3.2.2. 
Safety 
The safety endpoint in Phase 1 of the study is: 
x DLTs 
Additional safety endpoints in both Phases 1 and 2 of the study are: 
x Incidence of neutrophil and platelet engraftment failure. 
x Duration of cytopenia (i.e., absolute neutrophil count [ANC] ≤0.5×109/L; platelet count 
≤20×109/L). 
x Cumulative incidence of treatment-related mortality (TRM). 
x Transplant-related non-hematologic Grade 3 toxicity over time through Day 30, stratified 
by hematopoietic cell transplantation comorbidity index (HCT-CI).  
x Incidence of adverse events (AEs) and serious adverse events (SAEs). 
x Change from baseline in standard safety hematology and clinical chemistry test results. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a 2-part, international, multi-center, open-label study of salvage treatment with 
tinostamustine conditioning followed by ASCT in patients with relapsed/refractory MM. (ASCT 
is defined as salvage if the patient had already received a prior ASCT and undergoes a second 
ASCT after evidence of progressive disease [PD].) 
Phase 1 of the study employs a standard 3+3 dose escalation design with the objective of 
defining the DLTs of the tinostamustine conditioning regimen and defining the MTD and RP2D 
for use in the Phase 2 portion of the study. The initial dose of tinostamustine in the Phase 1 
portion of the study is 180 mg/m2, with escalation to 220, 260, and then 300 mg/m2 or higher 
planned. If the 180 mg/m2 dose level is not tolerable, then a lower tinostamustine dose of 
160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, with <33% of patients 
experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may be explored. The 
Safety Review Committee can make a decision to stop dose escalation or explore intermediary 
doses at any time. 
In Phase 2 of the study, all patients will receive tinostamustine at the RP2D administered in 
Phase 1 according to the same schedule.  
Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of Phase 2, up 
to 31 patients initially will be enrolled. Recruitment will continue during the evaluation period 
needed for Stage 1 of Phase 2. If ≤25 patients of these initial 31 patients experience a response, 
then no additional patients will be enrolled. However, if >25 patients in Stage 1 of Phase 2 
experience a response, then enrollment in this cohort will continue, with up to 71 patients 
enrolled. In Phase 2 of the study, all patients will receive tinostamustine at the RP2D 
administered in Phase 1 according to the same schedule. 
After provision of written informed consent, patients will be screened for study eligibility within 
28 days before Day 1 (the day of ASCT). Patients who have a minimum of 2×106 CD34+ 
cells/kg cryopreserved and are otherwise determined to be eligible, based on screening 
assessments, will be enrolled and receive the tinostamustine conditioning regimen. The 
tinostamustine dose will be administered 24 hours pre-ASCT (i.e., Day -1).  
On Day 1, ASCs will be administered intravenously (IV) according to standard institutional 
practice.  
Patients will receive standard supportive measures (including growth factor support post-ASCT, 
antimicrobial prophylaxis, red blood cell and platelet transfusion and treatment for neutropenic 
fever) according to standard institutional practice. 
During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 
Day 30 (±5 days) post-ASCT or until all transplant-related toxicity resolves. Patients will be 
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discharged from the study center once the following engraftment criteria are met: 
x Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
x Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days. 
Thereafter, patients are to be followed at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
4.2. 
Justification for the Study Design  
Goals of Phase 1 oncology studies include estimation of the initial safety and tolerability of a 
study drug, establishment of an MTD, and determination of a recommended range of doses for 
evaluation in future clinical studies, based on safety and PK (Ahn, 1998; Gatsonis, Greenhouse, 
1992; Dillman, Koziol, 1992); the primary objectives of the current study are consistent with 
those typical of Phase 1 oncology studies.  
Phase 1 of the study employs a traditional 3+3 dose escalation design. The dose escalation 
scheme to be followed is based on a modified Fibonacci sequence schema, which is commonly 
employed in Phase 1 dose-finding oncology studies (Storer, 1989).  
After identification of the RP2D in the Phase 1 portion of the study, the potential efficacy of 
conditioning with tinostamustine followed by ASCT will be investigated in the Phase 2 portion 
of the study. Phase 2 utilizes a Simon 2-stage minimax design, a common design in Phase 2 
oncology clinical studies by which the expected sample size is minimized if the treatment 
regimen has minimal activity (Simon, 1989).  
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5. 
STUDY POPULATION 
Patients with relapsed/refractory MM who have received prior ASCT after standard first-line 
induction treatment are planned to be enrolled. 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible for study entry: 
1. Patient has MM and: 
a. Has received prior ASCT after standard first-line induction treatment. 
b. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18 months 
in Phase 2. 
Progression Free Interval is defined as the time from date of ASCT to PD. 
c. Received treatment with ≤3 prior lines of therapy. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. 
When patients have undergone sequential phases of treatment without intervening 
progression, such as induction, collection of peripheral blood stem cells, 
transplantation and consolidation/maintenance, this is considered to be 1 line of 
treatment. A new line of therapy is initiated as a result of PD or relapse (Garderet et 
al, 2017). 
2. CR, PR, or minimal response (MR) to salvage chemotherapy, as determined by the 
International Myeloma Working Group (IMWG) criteria.  
3. Is, in the Investigator’s opinion, a candidate for consolidation therapy with tinostamustine 
followed by ASCT. (Note that patients planned to receive tandem ASCT are not eligible 
for the Phase 1 portion of the study.) 
4. Has available autologous PBSC product with CD34 cell dose ≥2×106 cells/kg. The 
product could be from a collection prior to first ASCT or later second collection.  (Note 
that, although not required, in Phase 1, the Investigator should consider enrolling patient 
with a large number of available PBSCs to permit subsequent ASCT, as patients in 
Stage 1 may received a dose lower than that determined to be effective.) 
5. Age 18-75 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score <3 at Screening. 
7. Creatinine clearance ≥40 mL/min, as determined by a local laboratory using the 
Cockcroft-Gault equation within 28 days before ASCT. 
8. Left ventricular ejection fraction (LVEF) ≥40% within 28 days before ASCT. 
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9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), 
forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) >50% 
predicted within 28 days before ASCT. 
10. Adequate liver function, as defined by an alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN) and bilirubin ≤1.5 × 
ULN within 28 days before ASCT.  
11. Potassium within the local laboratory’s normal range. (Potassium supplementation is 
permissible.) 
5.2. 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study entry: 
1. History of central nervous system (CNS) disease involvement. 
2. Primary or secondary plasma cell leukemia at any time point prior to transplant 
2. Myocardial infarction (MI) or stroke within 6 months before Screening.  
3. Uncontrolled acute infection. 
4. HCT-CI >6 points. 
5. Concurrent malignant disease with the exception of treated basalioma/spinalioma of the 
skin or early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment 
for other malignancies (not listed above) must have been terminated at least 24 months 
before registration and no evidence of active disease shall be documented since then. 
6. Major coagulopathy or bleeding disorder. 
7. Other serious medical condition that could potentially interfere with the completion of 
treatment according to this protocol or that would impair tolerance to therapy or prolong 
hematological recovery. 
8. Lack of cooperation to allow study treatment as outlined in this protocol. 
9. Pregnancy or lactating female patients.  
10. The use of any anti‐ cancer investigational agents within 21 days prior to the expected 
start of trial treatment and interval of 14 days to last administration of salvage treatment. 
11. Receiving treatment with drugs known to prolong the QT/QTc interval. 
12. QTc interval (Fridericia’s formula) >450 msec, based on the mean of triplicate Screening 
12-lead ECGs.   
 
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5.3. 
Source of Patients 
This will be a multinational, multicenter study. Each study center is required to obtain local 
Institutional Review Board (IRB)/Ethics Committee (EC) and national regulatory approval to 
conduct the study before enrollment of patients may commence. Patients meeting the entry 
criteria who are known or referred to the study center will be eligible for enrollment. 
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6. 
STUDY CONDUCT 
6.1. 
Patient Identification and Enrollment 
To ensure accurate and timely monitoring of patient enrollment, the following procedures will be 
implemented: 
x Patients who are candidates for enrollment into the study will be assigned a sequential 
and unique patient number by the Investigator after the patient has provided written 
informed consent. Once a patient number has been assigned, it cannot be reused. 
x Patients who have provided written informed consent will be evaluated for eligibility by 
the Investigator to ensure that the entry criteria (see Section 5.1 and Section 5.2) have 
been satisfied and that the patient is eligible for participation in this clinical study. An 
eligibility form will be provided by the Sponsor, or designee for this evaluation. 
x The Investigator or the Investigator’s research staff will provide eligibility information to 
the Sponsor or designee. After confirmation, the Sponsor or designee will provide the 
Investigator with written verification of each patient’s enrollment. 
x No patient may be enrolled prior to confirmation of a patient’s eligibility by the Sponsor 
or designee. 
x Patients who are enrolled but not treated with tinostamustine followed by ASCT will be 
replaced.  
x Investigators will be notified by the Sponsor or designee when enrollment in a given dose 
cohort / study part is closed and enrollment into the next dose cohort / study part can 
begin. (Investigators will be consulted in all dose escalation decisions.) 
x Investigators will be notified by the Sponsor or designee if the study is placed on 
administrative hold, when it is completed, or is closed to further patient enrollment. 
6.2. 
Patient Management 
All patients must provide written informed consent before any samples are collected or 
evaluations performed in this study that are not part of standard patient care. Patients will be 
evaluated for study eligibility during the Screening period, within 28 days before baseline 
(Day 1; the Day of ASCT).  
Patients who are determined to be eligible, based on Screening assessments, will return to the 
clinic to receive the tinostamustine conditioning regimen; the tinostamustine dose will be 
administered 24 hours pre-ASCT (on Day -1). 
On Day 1, ASCs will be administered IV according to standard institutional practice.  
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During in-patient hospitalization, patients will be assessed daily for toxicity through Month 1 
Day 30 (±5 days) post-ASCT or until all transplant-related toxicity resolves. Patients will be 
discharged from the study center once engraftment criteria are met (see Section 8.3). 
Thereafter, patients are to be followed at Month 2 Day 60 (±5 days) and Day 100 (±7 days).  
6.3. 
Patient Adherence 
All patients are required to adhere to the protocol-specified dosing and visit schedules. If a 
patient misses a scheduled visit, attempts should be made to reschedule the visit within the visit 
windows specified in Table 1. Failure to attend scheduled study visits may result in 
discontinuation from the study. 
6.4. 
Treatment Discontinuation Criteria 
Once tinostamustine has been infused it will be medically negligent to stop transplant and 
supportive therapy for the particular patient.  In the event of consent withdrawal during or 
following conditioning or the development of complications that, in the Investigator’s opinion, 
puts the patient at risk with continued protocol-specified treatment, the Medical Monitor should 
be contacted immediately to discuss management of the patient.  
6.5. 
Study Discontinuation Criteria 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
x Patient non-adherence to protocol requirements. 
x Patient unwillingness to continue in the study. 
x Any other reason, based upon the medical judgment of the Investigator. 
The reason for study withdrawal is to be documented in the patient’s source documents and 
electronic case report form (eCRF). 
6.6. 
Study Completion 
A patient is considered to have completed the study if they complete the Day 100 (±7 days) visit 
and a confirmatory response assessment between D107 visit and D130 visit, the latest.  
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6.7. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest the study 
should be halted, then this can happen only after appropriate consultation between the Sponsor 
and Investigator. Conditions that may warrant study termination include, but are not limited to: 
x The discovery of any unexpected, significant, or unacceptable risk to the patients enrolled in 
the study. 
x Failure of the Investigator to enter patients at an acceptable rate. 
x Insufficient adherence to the protocol requirements. 
x A decision on the part of the Sponsor to suspend or discontinue development of 
tinostamustine. 
6.8. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study. The Investigator at each 
study center is responsible for ensuring the accuracy and completeness of all research records, 
the accountability of study drug, and the conduct of clinical and laboratory evaluations as 
outlined in the protocol. The Investigator is responsible for ensuring that the clinical study is 
performed in accordance with the Declaration of Helsinki and the International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidance documents. 
6.9. 
Safety Committee 
A Safety Committee will be involved in the conduct of this study. The Safety Committee will be 
comprised of Sponsor personnel, the Medical Monitor, the Investigator or representative thereof 
at each active study center, and a biostatistician (as needed). Ad hoc participants may be part of 
the committee at the request of the Sponsor or other Safety Committee members. The Safety 
Committee has the responsibility for monitoring the clinical study’s progress and the safety of 
the participating patients. The Safety Committee will evaluate study conduct during the course of 
the clinical study, based upon data defined for this clinical study.  
In Phase 1, the Safety Committee will review all safety data from all patients enrolled in each 
cohort to confirm any DLTs that were experienced and make a determination regarding 
enrollment in the next cohort. If a DLT necessitates enrollment of additional patients into a 
cohort, the Safety Committee will review all of the safety data for that cohort after those 
additional patients before a determination regarding enrollment in the next cohort is made. Based 
on evaluation of the data, the Safety Committee may decide that enrollment at an intermediate 
dose level not specified in this protocol may take place.  
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In addition, after identification of the MTD, the Safety Committee will review all safety data 
collected to date to confirm that no unexpected, significant, or unacceptable risk to patients 
enrolled in the study has been discovered.  
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Mundipharma EDO or its designee will supply tinostamustine to the pharmacies at all 
participating study centers. All study drug must be stored in a safe and locked place with no 
access by unauthorized personnel.  
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The drug substance 
is a class 4 cytotoxic agent and should be handled with care by experienced health care 
professionals. 
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Study drug will be labeled in accordance with applicable regulatory requirements. Study drug 
labels will not contain any statement that is false or misleading in any manner or represent that 
the study drug is safe or effective for the purposes for which it is being investigated.  
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Tinostamustine vials are stored 
  
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The Investigator or delegate will maintain accurate records of receipt and condition of study 
drug, including dates of receipt. In addition, accurate records will be kept of the date 
administered, quantity administered, and the patient to whom study drug was administered. Any 
reasons for departure from the protocol-specified dispensing regimen must also be recorded.  
The Investigator is responsible for the accountability of all used and unused study drug 
containers and unused study drug. The site identification (ID) number and patient initials and ID 
number are to be recorded on each study drug accountability log. Each time study personnel 
dispense study drug for a patient, they are to record the date dispensed, amount dispensed, and 
their initials. Study personnel are to monitor the inventory of clinical supplies and maintain a 
count of all used and unused supplies.  
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A Clinical Research Associate (CRA) will review study drug accountability records during 
routine monitoring visits. At the completion of the study, there will be a final reconciliation of all 
study drug. 
7.5. 
Study Drug Dose 
In Phase 1 of the study, the starting dose of tinostamustine is 180 mg/m2, with escalation to 220, 
260, and then 300 mg/m2 planned. If the 180 mg/m2 dose level is not tolerable, then a lower 
tinostamustine dose of 160 mg/m2 will be explored. Furthermore, if the 300 mg/m2 is tolerable, 
with <33% of patients experiencing a DLT at this dose level, a dose higher than 300 mg/m2 may 
be explored. The Safety Review Committee can make a decision to stop dose escalation or 
explore intermediary doses at any time. 
In Phase 2, patient will receive tinostamustine at the RP2D identified in Phase 1.  
7.5.1. 
Dose Escalation Procedure 
In Phase 1, up to 3 patients initially are to be enrolled in each cohort. The first patient enrolled in 
the initial cohort must complete the study through engraftment without a ≥Grade 3 toxicity or 
through 30 days post-ASCT without a DLT, whichever occurs first, before additional patients 
may be enrolled in that initial cohort. (If the first patient experiences a DLT, then a lower dose 
will be explored for the second patient and so on.) 
x If the first patient does not experience a DLT (see Section 7.5.2) or experiences 
engraftment without a ≥Grade 3 toxicity, the next 2 patients may be enrolled 
simultaneously. 
After 3 patients in a cohort complete the study through engraftment without a ≥Grade 3 toxicity 
or through 30 days post-ASCT without a DLT, whichever occurs first, and have safety 
evaluations performed through that time, and: 
x None of these 3 patients experience a DLT (see Section 7.5.2), then enrollment of the 
next cohort may commence with approval from the Safety Committee. 
x 1 of 3 patients within a cohort experiences a DLT (see Section 7.5.2), then up to 
3 additional patients are to be enrolled sequentially at that dose level. If none of the 
additional 3 patients has a DLT (i.e., 1 of 6 patients has a DLT), then enrollment at the 
next scheduled dose may commence with approval from the Safety Committee. 
x If t2 patients within a cohort experience a DLT (see Section 7.5.2), then the DLT dose 
level will have been reached and the previous lower dose level will be considered the 
MTD. (If t2 patients in the initial dose cohort experience DLTs, then the dose will be 
reduced to one level lower and the same procedure will be followed.) 
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A total of 6 patients are planned to be treated at the MTD to confirm the RP2D before enrollment 
of patients in Phase 2 of the study. If the MTD is not confirmed at this stage, the dose will be 
reduced to one level lower and the same procedure will be followed. 
Note that enrollment in the next dose cohort can begin only when the last patient enrolled in the 
current dose cohort completes the study through engraftment without a ≥Grade 3 toxicity or 
through 30 days post-ASCT without a DLT, whichever occurs first,, provided that <2 patients in 
the current dose cohort experienced a DLT.  
Although decisions regarding dose escalation will be made based on review of data through 
Day 30 post-ASCT, safety data will also be collected from all patients continuing in the study 
and this will be reviewed periodically by the Safety Committee. Any detected toxicity may 
necessitate further refinement of the RP2D. 
7.5.2. 
Definition of Dose-limiting Toxicity 
Toxicity will be assessed by the Investigator using the US NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version 4.03. The centralized laboratory assessment of ECGs will 
be used for the determination of DLT. 
In Phase 1 of the study, DLT is defined as the occurrence of any of the following events 
occurring within 30 days post-ASCT that are considered by the Investigator to be at least 
possibly related to tinostamustine: 
x Delayed engraftment (>30 days after ASCT). Engraftment will be considered delayed if 
the subject has not met criteria for both neutrophil and platelet engraftment:  
- Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
- Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days.  
x QTcF >500 msec or >60 msec increase from baseline, with a duration of >30 minutes, 
based on the mean of triplicate 12-lead ECGs, or ≥Grade 3 QTcF interval prolongation 
accompanied by ventricular arrhythmia.  
Baseline QTcF interval will be the mean value determined during triplicate ECG(s) at 
Day -1 (-1), before study drug administration confirmed by the cental laboratory. 
x Grade 4 non-hematologic toxicity 
x Grade 3, non-hematologic toxicity related to treatment, with the exception of: 
- Nausea or vomiting  
- Diarrhea  
- Fatigue, dehydration, or glucose intolerance 
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 Skin rash, dry skin, or pruritus responsive to topical or systemic steroids 
 Fever (>40ºC for ≤24 hours) 
 Infection 
 Dyspnea, hypoxia, or pneumonitis 
 Abdominal pain 
 Dysphagia, oral mucositis, oral pain, or anorexia 
 Flu-like syndrome 
 Engraftment syndrome  
 Weight loss 
 Pain, pain in extremity, headache, or insomnia 
 Hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, or hypophosphatemia 
 Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
bilirubin, or alkaline phosphatase 
 Alopecia 
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The MTD is defined as the highest dose level at which ≤1 of 6 patients experiences DLT through 
30 days post-ASCT. 
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The RP2D may be equal to or higher than the preliminary MTD, but less than the non-tolerated 
dose (i.e., the dose at which ≥2 of 6 patients experienced DLT). The RP2D will be determined in 
discussion with the Sponsor, Medical Monitor, and Investigators.  
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For administration, tinostamustine powder is reconstituted with 20 mL saline (0.9%) and the 
solution must be further diluted with saline (0.9%) to a final volume of 50 mL. 
 
 
Please refer to the study specific Pharmacy Manual to ensure the correct preparation of 
tinostamustine. 
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Tinostamustine is to be administered IV through a peripheral vein over 1 hour. 
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All prescription and non-prescription medications and therapies, including pharmacologic doses 
of vitamins, herbal medicines, or other non-traditional medicines, taken from 28 days prior to the 
first dose of tinostamustine through Day 100 (±7 days) must be recorded in the eCRF. 
Concomitant medications will be documented as administered pre-conditioning (i.e., pre-
tinostamustine); during conditioning (i.e., after the start of the first tinostamustine infusion 
through immediately before the start of autologous stem cell [ASC] infusion); or after ASCT 
(i.e., after the start of ASC infusion). 
On PK sample collection days (Table 1), both the date and time of concomitant medications and 
therapies must be recorded. 
The Investigator should contact the study medical monitor with any questions or clarifications 
regarding concomitant medications. 
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7.8.1. 
Prohibited Medications 
The following medications and treatments are prohibited during study participation: 
x Any investigational agent or device other than tinostamustine, including agents that are 
commercially available for indications other than MM that are under investigation for the 
treatment of MM. 
x Any anti-neoplastic treatment with activity against MM.  
x Medications known to prolong the QT/QTc interval, will be excluded. The use of other 
concomitant medications that present a low risk of QT/QTc prolongation may be 
considered, with the approval of the Medical Monitor. (Refer to the crediblemeds list of 
drugs with known risk of TdP: http://crediblemeds.org.) 
7.8.2. 
Permitted Medications and Supportive Therapies 
Medications and treatments other than those specified in Section 7.8.1, including palliative and 
supportive care for disease-related symptoms, are permitted during the study. Patients should be 
closely monitored, and treatment is to be instituted for disease-related symptoms, as appropriate. 
Patients may receive the following supportive care:   
x IV hydration and anti-emetics, in accordance with institutional guidelines. 
x Growth factor support with pegfilgrastim or equivalent agent post-ASCT, in accordance 
with institutional guidelines.  
x Standard supportive care, in accordance with institutional guidelines, including blood 
product transfusions, antimicrobial prophylaxis (e.g., anti-bacterial, Pneumocystis carinii, 
anti-fungal, herpes simplex virus/varicella zoster virus), and treatment for febrile 
neutropenia. 
x Bisphosphonates may be administered after ASCT according to local institutional 
practice. 
x After adequate blood count recovery (ANC >1.0×109/L and platelet count >80×109/L) as 
well as resolution of mucositis and fever, if present, radiation may be administered for the 
following indications after consultation with the Medical Monitor: 
- Palliation of pain from bone lesions 
- Prevention of pathologic fractures 
- Relief of spinal cord compression or nerve root compression 
The radiation oncologist is to determine the dose and duration of radiation to be 
administered. Radiation to the liver or lungs should be avoided.  
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7.9. 
Blinding 
This is an open-label study; no blinding methods will be employed. 
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8. 
TRANSPLANT PROCEDURES 
8.1. 
Conditioning 
See Section 7.6 for details regarding tinostamustine preparation and administration. 
8.2. 
ASCT Infusion 
Patients will receive ASCs on Day 1. The ASCs will be infused via a central venous catheter 
using standard blood infusion tubing, per standard institutional practice. 
8.3. 
Engraftment 
During in-patient hospitalization, patients will be assessed daily for hematologic engraftment, 
starting on the first day the ANC is <0.5×109/L until and including the day engraftment criteria 
are met, as follows: 
x Neutrophil engraftment is defined as the first of 3 consecutive days with ANC 
>0.5×109/L.  
x Platelet engraftment will be defined as the first of 3 consecutive days of platelet count 
>20×109/L without platelet transfusion in the prior 7 days. 
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9. 
STUDY ASSESSMENTS 
9.1. 
Baseline Assessments 
9.1.1. 
Informed Consent 
All patients must provide written informed consent before any samples are collected or 
evaluations performed in this study that are not part of standard patient care.  
9.1.2. 
Demographics 
Patient demographics, including age, sex, race, and ethnicity, are to be documented in the source 
documents and in the eCRF at Screening.  
9.1.3. 
Medical History, Including Cancer History 
A complete medical history, including prior and concomitant illnesses and conditions as well as 
prior surgeries and other procedures, is to be documented in the source documents and in the 
eCRF at Screening. MM history, including the date of diagnosis and details regarding prior 
ASCT and all other previous treatment for MM and best response to such treatments, also is to 
be documented and recorded in the eCRF. 
9.1.4. 
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) 
The HCT-CI is a validated comorbidity index that comprises 17 different categories of organ 
dysfunction (Sorror et al. 2007; Maruyama et al. 2007; Barba et al. 2010; Frina et al. 2009). 
Positive findings are summated into a total score. The HCT-CI provides information with regard 
to the overall as well as non-relapse mortality risk a patient is likely to experience after SCT. 
HCT-CI score is to be documented in the source documents and in the eCRF at Screening.  
The HCT-CI is accessible at:  http://www.hctci.org/Home/Calculator.  
9.1.5. 
Prior and Concomitant Medications 
All prior medications and supplements the patient received within 28 days before baseline and all 
medications and supplements the patient receives through Day 100 are to be documented in the 
source documents and in the eCRF. Concomitant medications will be documented as 
administered pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., after the start 
of the first tinostamustine infusion through immediately before the start of ASC infusion); or 
after ASCT (i.e., after the start of ASC infusion). 
9.1.6. 
Echocardiogram or Multi-gated Acquisition Scan 
LVEF is to be determined by multi-gated acquisition scan or echocardiography during 
Screening. 
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9.1.7. 
Pulmonary Function Testing 
The following PFTs are to be measured during Screening 
x FEV1 
x FVC 
x DLCO 
Patients who have difficulty making an appropriate seal on the mouthpiece to perform PFTs 
effectively should be fitted with a facial mask for PFT measurements. 
9.1.8. 
Screening Serologies 
Blood samples for infectious disease marker testing, including, at a minimum, human 
immunodeficiency virus (HIV) types 1 and 2, hepatitis B virus (HBV) panel (HBV surface 
antigen, HBV surface antibody, HBV core antibody, HBV e-antigen), hepatitis C virus (HCV), 
Treponema pallidum, cytomegalovirus, and Epstein-Barr virus, are to be collected during 
Screening. Any patient with a positive result is not eligible for study participation.  
9.1.9. 
Pregnancy Testing 
Serum or urine E-human chorionic gonadotropin (hCG) pregnancy testing is to be performed for 
female patients of childbearing potential (i.e., premenopausal or not surgically sterile) during 
Screening. Any patient with a positive result is not eligible for study participation. Pregnancy 
testing is to be repeated any time pregnancy is suspected.  
9.2. 
Safety Measurements 
9.2.1. 
Physical Examination, 
Physical examinations are to be performed at each study center visit. Complete physical 
examinations are to be performed at the time points designated in Table 1. The complete physical 
examination includes assessment of the following: 
x General appearance 
x Head, eyes, ears, nose, and throat  
x Cardiovascular system 
x Respiratory system 
x Gastrointestinal system (abdomen) 
x Lymphatic system 
x Musculoskeletal system 
x Skin 
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x Psychiatric 
x Neurological – A complete neurologic examination, including assessment of mental 
status, memory, cranial nerves, motor function, and reflexes, is to be performed as part of 
the complete physical examination.  
Targeted (i.e., symptom-directed) physical examinations are to be conducted at the time points 
designated in Table 1. 
Abnormal physical examination findings that are considered by the Investigator to be clinically 
significant are to be reported as an AE, if the finding represents a change from baseline. 
9.2.2. 
Height and Weight 
Height is to be measured for all patients during Screening. 
Body weight is to be measured during Screening and at the time points designated in Table 1. 
The patient’s height documented during Screening and weight documented prior to the 
commencement of tinostamustine on Day -1 are to be used to calculate the tinostamustine dose.  
9.2.3. 
ECOG Performance Status 
ECOG performance status is to be determined at the time points designated in Table 1. The 
ECOG performance status scale, with corresponding Karnofsky performance status score 
equivalents, is presented in Table 4. 
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Table 4: 
Eastern Cooperative Oncology Group Performance Status Scale, with 
Equivalent Karnofsky Performance Status Scores 
ECOG1 
Karnofsky2 
Score 
Criterion 
% 
Criterion 
0 
Normal activity 
100 
Normal; no complaints; no evidence of 
disease 
 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
Symptoms but ambulatory 
80 
Normal activity with effort; some signs or 
symptoms of disease 
 
 
70 
Cares for self; unable to carry on normal 
activity or do active work 
2 
In bed <50% of time 
60 
Requires occasional assistance but is able 
to care for most of his/her needs 
 
 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed >50% of time 
40 
Disabled, requires special care and 
assistance 
 
 
30 
Severely disabled; hospitalization is 
indicated though death is not imminent 
4 
100% bedridden 
20 
Very sick; hospitalization is necessary 
 
 
10 
Moribund; fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
1 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
2 
Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale:  an examination of its reliability 
and validity in a research setting. Cancer. 1984;53:2002-2007. 
9.2.4. 
Vital Signs 
Vital signs, including blood pressure, pulse and respiration rates, and body temperature, are to be 
measured at the time points designated in Table 1. Pulse rate and blood pressure will be 
measured with the patient in a sitting position after a 5-minute rest. 
Vital signs abnormalities that are considered by the Investigator to be clinically significant are to 
be reported as AEs, if the finding represents a change from baseline. 
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9.2.5. 
Holter Monitoring 
Continuous Holter monitoring will be performed on Day -1, the day of tinostamustine 
administration. Holter monitoring will commence 15 minutes prior to the start of the infusion on 
Day -1 and will continue through 24 hours following the end of infusion. 
Patients should be resting comfortably in the supine or semisupine position for 15 minutes prior 
to each of the following timepoints: 0 [before start of infusion] then after start of the infusion at 
15, 30, 45, 60 and 75 minutes and 3, 6, and 24 hours following the start of the infusion. 
At time 0 and at all time points after infusion, ECGs readings will be extracted for establishment 
of baseline and for the purposes of Dose Limiting Toxicities determination and for cardiac safety 
analyses. 
The Holter monitor flashcards will be sent to eResearch Technology, Inc., for processing. The 
analysis methodology will be described in a separate ECG cardiac safety statistical analysis plan. 
Note that because the ECG recordings are stored on flashcards, results will not be available in 
“real time” at the study center. 
The ECGs extracted from the Holter monitoring will be used for the determination of DLTs. 
9.2.6. 
12-Lead Electrocardiogram 
A triplicate ECG will be performed during Screening to determine patient eligibility for the 
study. Furthermore, on Day -1 (-1 day), a triplicate ECG is to be performed before study drug 
administration and a single ECGs will be performed at 30 and 60 minutes after the start of study 
drug administration for assessment by the site. Another single ECG will be performed at visit on 
D30 (±5 days). ECGs are to be repeated by the Investigator, as clinically indicated. 
ECGs (12-lead) are to be performed in after the patient is supine for 5 minutes.  
All screening ECGs will be reviewed centrally. Regarding other 12-lead ECGs: the Investigator 
or the Sponsor may request expedited central review of ECGs, as clinically indicated. ECGs will 
be reviewed centrally. The Investigator or the Sponsor may request expedited central review of 
ECGs, as clinically indicated. 
The Investigator’s interpretation of ECGs is to be used for patient management during the study; 
the central reader interpretation of ECGs extracted from Holter monitoring will be used to 
determine all ECG data for study endpoints including baseline QTcF interval for cardiac safety 
analyses and DLTs. 
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9.2.7. 
Safety Laboratory Tests 
9.2.7.1. 
Hematology, Serum Chemistries, and Urinalysis 
Blood samples are to be collected for assessment of hematology, coagulation studies, and clinical 
chemistry parameters  and urine samples for urinalysis, according to the schedule defined in 
Table 1. Laboratory samples are to be collected after vital signs are measured. 
The following safety laboratory parameters will be measured: 
Hematology 
 
x 
Hematocrit 
x 
Neutrophils 
x 
Hemoglobin 
x 
Lymphocytes 
x 
Red blood cell count 
x 
Monocytes 
x 
White blood cell count 
x 
Eosinophils 
x 
Platelet count 
x 
Basophils 
Serum Chemistries 
 
x 
ALT 
x 
Alkaline phosphatase 
x 
AST 
x 
Bicarbonate 
x 
Bilirubin (total, direct, and indirect) 
x 
Calcium 
x 
Magnesium 
x 
Chloride 
x 
Glucose 
x 
Lactate dehydrogenase 
x 
Phosphate 
x 
Potassium 
x 
Sodium 
x 
Total protein 
x 
Creatinine* 
x 
Blood urea nitrogen 
x 
Uric acid 
 
*To be fractionated if abnormal. 
Coagulation Studies 
 
x 
Prothrombin time and/or International 
normalized ratio 
x 
Activated partial thromboplastin time 
 
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Urinalysis 
 
x 
Color 
x 
pH 
x 
Specific gravity 
x 
Protein 
x 
Glucose 
x 
Ketones 
x 
Blood 
 
Safety laboratory tests may be repeated as necessary during treatment at a schedule determined 
by the Investigator, based on the patient’s clinical status.  
Laboratory abnormalities that are considered by the Investigator to be clinically significant are to 
be reported as AEs, if the finding represents a change from baseline. 
9.2.8. 
Adverse Events 
9.2.8.1. 
Definitions 
9.2.8.1.1. Adverse Event 
An AE is defined in the ICH Guideline for GCP as “any untoward medical occurrence in a 
patient or clinical investigation patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment” (ICH E6:1.2). 
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) should 
be considered an AE if there is either an increase in severity, frequency, or duration of the 
condition or an association with significantly worse outcomes. 
Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AEs. 
In the case of death, only record “Fatal” for the event causing death. AEs that are ongoing at the 
end of the study or time of death are to be noted as “continuing.” Classification of AEs is to be 
done by the Investigator according to the NCI CTCAE, version 4.03. 
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual patient represents a significant change from baseline. In general, 
abnormal laboratory findings without clinical significance (based on the Investigator’s judgment) 
should not be recorded as AEs; however, laboratory value changes requiring therapy are 
considered AEs. 
9.2.8.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of safety reporting, “reasonable possibility” and/or at least 
possibly related means there is evidence to suggest a causal relationship between the drug and 
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the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by a drug. 
9.2.8.1.3. Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
x is fatal 
x is life-threatening (i.e., places the patient at immediate risk of death) 
x requires in-patient hospitalization or prolongation of existing hospitalization 
x results in persistent or significant disability/incapacity 
x is a congenital anomaly/birth defect 
x is an important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definitions for 
SAEs. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any AE that 
does not meet one of the definitions of serious (i.e., emergency room visit, outpatient surgery, or 
requires urgent investigation) may be considered by the Investigator to meet the “important 
medical event” criterion for classification as an SAE. 
9.2.8.1.4. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, if 
an Investigator’s Brochure is not required or available, is not consistent with the risk information 
described in the General Investigational Plan or elsewhere in the current application, as 
amended.  
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9.2.8.1.5. Serious and Unexpected Suspected Adverse Reaction 
A serious and unexpected suspected adverse reaction (SUSAR) is any event that meets all 3 of 
the following definitions: 
1) suspected adverse reaction (Section 9.2.8.1.2); 
2) serious (Section 9.2.8.1.3); and  
3) unexpected (Section 9.2.8.1.4). 
9.2.8.2. 
Adverse Event Assessment 
All AEs will be collected and recorded from the time written informed consent is obtained 
through Day 100 (±7 days), or after the end of the study, if thought to be related to study drug. 
This includes AEs the patient reports spontaneously, those observed by the Investigator, and 
those elicited by the Investigator in response to open-ended questions during scheduled study 
visits.  
Each AE is to be assessed by the Investigator with regard to the following categories. 
Serious/Non-Serious 
AEs that meet the criteria specified in Section 9.2.8.1 are to be considered serious. 
Relationship to Study Drug 
The relationship of each AE to study drug is to be assessed by the Investigator according to 
categories in Table 5. 
Table 5: 
Criteria for Determination of Adverse Event Relationship to Study Drug 
Relationship Between Study Drug and AE: 
AE (is): 
Category 
None 
Unlikely 
Possibly 
Likely 
Definitely 
Clearly the result of an external factor 
Yes 
No 
No 
No 
No 
Probably/possibly the result of another 
factor 
No 
Yes 
Yes 
No 
No 
Has a chronological relationship with the 
time of administration and/or represents a 
known reaction to Study Drug 
No 
No 
Yes 
Yes 
Yes 
Disappears or decreases after 
discontinuation of the Study Drug 
NA 
NA 
NA 
Yes 
Yes 
Recurs on renewed administration 
(re-challenge) 
No 
No 
NA 
NA 
Yes or 
NA** 
**A re-challenge is not required; if done, re-challenge would be expected to be positive. 
NA = not applicable 
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Intensity 
The intensity of each AE is to be assessed by the Investigator according to the NCI CTCAE, 
version 4.03. If the AE is not included in the NCI CTCAE, version 4.03, then the Investigator is 
to determine the intensity of the AE according to the following criteria: 
x Mild (Grade 1): Asymptomatic or mild symptoms:  clinical or diagnostic observations only; 
intervention not indicated. 
x Moderate (Grade 2): Minimal, local, or non-invasive intervention indicated; limited age-
appropriate instrumental activities of daily living. 
x Severe (Grade 3): Severe or medically significant but not immediately life threatening:  
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living; incapacitating with inability to work or perform normal daily 
activity. 
x Life-threatening (Grade 4): consequences:  urgent intervention indicated.  
x Death (Grade 5) related to an AE. 
9.2.8.3. 
Recording Adverse Events 
All AEs occurring from the from the time written informed consent is obtained through the Day 
100 (±7 days) visit are to be recorded in the source documents and in the eCRF. AEs will be 
documented as occurring pre-conditioning (i.e., pre-tinostamustine); during conditioning (i.e., 
after the start of the first tinostamustine infusion through immediately before the start of ASC 
infusion); or after ASCT (i.e., after the start of ASC infusion). All AE reports are to contain the 
following details regarding the AE:  a brief description, onset date, duration, intensity, treatment 
required, relationship to study drug, study drug action taken, outcome, and whether the event is 
classified as serious. 
9.2.8.4. 
Reporting Serious Adverse Events 
SAEs will be collected and recorded throughout the study period, beginning with the signing of 
the informed consent form (ICF) through the Day 100 (±7 days) visit, or after the end of the 
study if thought to be related to study drug.  
The Investigator must report all SAEs to the Sponsor within 24 hours of discovery.  
A completed SAE report is to be sent to the Medical Monitor’s attention within 24 hours of 
discovering the event. The initial report should include at least the following information: 
x Patient’s ID number; 
x Description and date of the event; 
x Criterion for serious; and 
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x Preliminary assignment of causality to study drug.  
The Medical Monitor will contact the Investigator via telephone for follow-up information 
regarding the SAE, as appropriate. 
The Investigator, or designated party, should notify the appropriate IRB/EC of SAEs occurring at 
the study center and other AE reports received from the Sponsor, in accordance with local 
procedures and statutes. 
SAEs that are considered as possible or probably related to the investigational product, and as 
unexpected (i.e., SUSARs), will be reported to the concerned Competent Authorities (CAs) and 
IRBs/ECs by the Sponsor or Sponsor’s designee as required by applicable local regulations. Per 
regulation, any fatal or life-threatening SUSAR will be reported to the CAs/IRBs/ECs within 
7 calendar days, and additional information within an additional 8 calendar days. The Sponsor or 
Sponsor’s designee is required to submit any other SUSAR to the CAs/IRBs/ECs within 
15 calendar days of notification. The Sponsor or its designee is also responsible for notifying the 
investigational sites of all expedited SAEs. The Investigator must keep copies of all expedited 
SAE information including correspondence with the Sponsor on file.  
9.2.8.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be at least 
possibly related to study drug either until resolution or the Investigator assesses them as chronic 
or stable. This follow-up may extend after the end of the study. 
9.2.8.6. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB/EC all unanticipated problems involving 
risks to patients. This includes death from any cause and all SAEs reasonably or possibly 
associated with the use of Study Drug according to the IRB/EC’s procedures.  
The Sponsor will assess the severity and frequency of adverse drug reactions in adults versus 
pediatric patients, and will submit findings annually in the Development Safety Update 
Report/Annual Report. 
9.2.8.7. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only in 
the event of an emergency. The Investigator or other physician in attendance in such an 
emergency must contact the Medical Monitor as soon as possible to discuss the circumstances of 
the emergency. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the patient 
should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be noted in the eCRF. 
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9.2.8.8. 
Pregnancy 
Pregnancy is considered unlikely in this study, given the population of patients to be enrolled. 
Nonetheless, pregnancies occurring within 12 months after the patient’s last dose of 
tinostamustine will not be considered serious, but are to be reported using the same procedures as 
for SAEs described in Section 9.2.8.4.  
The patient is to be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling. 
The Investigator will follow the patient until completion of the pregnancy, and must notify the 
Medical Monitor of the outcome within 5 days. The Investigator will provide this information as 
a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such. 
Furthermore, all neonatal deaths that occur within 30 days of birth are to be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to tinostamustine should also be reported. 
9.3. 
Disease Assessments 
9.3.1. 
Myeloma Protein Measurements in Serum and Urine 
9.3.1.1. 
Serum 
Blood samples for quantitation of immunoglobulin (Ig) (IgA, IgG, and IgM are required; IgD 
and IgE are optional) and M-protein and assessment of M-protein by immunofixation in serum 
are to be collected from all patients at the time points designed in Table 1. Note that in the case 
of IgA MM, MM IgA values should be used. 
All samples will be analyzed by the local laboratory. Assessments of response will be evaluated 
by two independednt reviewers.  
9.3.1.2. 
Urine 
Twenty-four hour urine samples for quantitation of M-protein and assessment of M-protein by 
immunofixation are to be collected from all patients during Screening. For patients with positive 
findings at Screening, such samples also are to be collected at the time points designed in 
Table 1. Patients with negative Screening results need not provide urine samples for M-protein 
quantitation and assessment after Screening.  
All samples will be analyzed by the local laboratory. Assessments of response will be evaluated 
by two independednt reviewers.  
 
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9.3.2. 
Free Light Chain Testing 
Serum samples for free light chain (FLC) testing are to be collected from all patients during 
Screening and at the time points designed in Table 1. The free kappa/lambda ratio is to be 
recorded in the eCRF. 
A serum sample for FLC testing also is to be collected in order to confirm stringent complete 
response (sCR). 
9.3.3. 
Bone Marrow Examination 
Bone marrow aspiration to be performed for all patients during Screening, and for patients who 
achieve a CR, on Day 100 (±7 days) post-ASCT. Bone marrow aspiration and biopsy are to be 
repeated during treatment as clinically indicated. 
Approximately 5mL of the same sample (i.e., “first-pull”), collected in 
ethylenediaminetetraacetic acid (EDTA) tubes, will be used for assessment of MRD-N using 
next-generation flow cytometry.  
9.3.4. 
Skeletal Survey and Other Imaging Studies 
Skeletal surveys (plain radiographs, or any other method used as standard care at the site, of the 
skull, spine, ribs, pelvis, humeri and femora) are to be performed during Screening. If a skeletal 
survey has been performed within 3 months before Baseline, then this evaluation need not be 
repeated during Screening.  
A skeletal survey is to be repeated during the study as clinically indicated.  
Other appropriate imaging studies (e.g., magnetic resonance imaging, CT, X-ray) to evaluate the 
patient’s disease are to be performed during Screening per standard of care, as determined by the 
Investigator. Appropriate imaging studies are to be repeated as necessary to confirm CR.  
9.3.5. 
Assessment of Disease Response 
The Investigator will perform tests that will allow evaluation of response to therapy according to 
the IMWG Criteria, as outlined in Table 6. Patients who are determined to have CR are then to 
have additional tests performed that will allow further characterization of the CR.  
Assessment of disease response using non-invasive procedures will be performed at the time 
points designed in Table 1. Appropriate imaging studies and bone marrow aspirates/biopsies 
must be repeated only in patients suspected of having a CR, based on non-invasive procedures. 
Table 6: 
IMWG Response Criteria 
Response 
IMWG Criteria 
Complete response (CR)1 
x 
Negative immunofixation of serum and urine, and 
x 
Disappearance of any soft tissue plasmacytomas, and 
x 
 <5% plasma cells in bone marrow 
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Response 
IMWG Criteria 
Stringent complete response (sCR) 
CR as defined above plus 
x 
Normal FLC ratio, and 
x 
Absence of clonal plasma cells (PC) by 
immunohistochemistry or 2-4 color flow cytometry. 
Immunophenotypic CR 
Stringent CR plus 
x 
Absence of phenotypically aberrant PC (clonal) in bone 
marrow (BM) with a minimum of one million of total BM 
cells analyzed by multiparametric flow cytometry (with >4 
colors) 
Molecular CR 
CR plus 
x 
Negative allele-specific oligonucleotide-polymerase chain 
reaction (ASO-PCR), sensitivity 10-5 
Very good partial response (VGPR)1 
x 
Serum and urine M-component detectable by immunofixation 
but not on electrophoresis, or 
x 
≥90% or greater reduction in serum M-component plus urine 
M component <100 mg per 24 hours 
Partial response (PR) 
x 
≥50% reduction of serum M-protein and reduction in 24-h 
urinary M-protein by ≥90% or to <200 mg per 24 hours 
x 
If the serum and urine M-protein are unmeasurable a ≥50% 
decrease in the difference between involved and uninvolved 
FLC levels is required in place of the M-protein criteria 
x 
If serum and urine M-protein are unmeasurable, and serum 
free light assay is also unmeasurable, ≥50% reduction in bone 
marrow plasma cells is required in place of M-protein, 
provided baseline percentage was ≥30% 
x 
In addition to the above criteria, if present at Baseline, ≥50% 
reduction in the size of soft tissue plasmacytomas is also 
required 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease. 
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Response 
IMWG Criteria 
Progressive disease (PD)2 
x 
Increase of 25% from lowest response value in any one or 
more of the following: 
x 
Serum M-component (absolute increase must be ≥0.5 g/dL) 
and/or 
x 
Urine M-component (absolute increase must be ≥200 mg/24 
hours) and/or 
x 
Only in patients without measurable serum and urine M 
protein levels: the difference between involved and 
uninvolved FLC levels (absolute increase must be >10 mg/dL) 
x 
Only in patients without measurable serum and urine M 
protein levels and without measurable disease by FLC levels, 
bone marrow plasma cell percentage (absolute % must be 
>10%) 
x 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas 
x 
Development of hypercalcemia (corrected serum calcium 
>11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder 
Source:. Rajkumar, et al. Blood 2011;117(18):4691-5. 
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution 
of any new therapy; complete response and PR and SD categories also require no known evidence of progressive or new bone 
lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether 
disease at Baseline was measurable on serum, urine, both, or neither. Radiographic studies are not required to satisfy these 
response requirements. Bone marrow assessments need not be confirmed. For progressive disease, serum M-component 
increases of ≥1 g/dL are sufficient to define relapse if starting M-component is ≥5 g/dL. 
1 Note clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum 
FLC levels: CR in such patients a normal FLC ratio of 0.26-1.65 in addition to CR criteria listed above. VGPR in such patients 
requires in addition a >90% decrease in the difference between involved and uninvolved free light chain FLC levels. 
2 Note clarifications to IMWG criteria for coding PD: Clarified than bone marrow criteria for progressive disease are to be used 
only in patients without measurable disease by M protein and by FLC levels. Clarified that “25% increase” refers to M protein, 
FLC, and bone marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia. Note that the 
“lowest response value” does not need to be a confirmed value. 
The Investigator’s assessment of disease response will be used for patient management during the study. 
Confirmation of responses should be obtained for biochemical markers but is not necessary for bone 
marrow or imaging studies. The confirmatory tests should be performed by Day 130. The response date is 
not the date of confirmation but the initial date when the assessment met the end point. In other words, the 
second test is confirmatory. If the result is not confirmed by a second evaluation, the status is either non-
evaluable and the prior disease status remains valid.   
9.3.6. 
Independent Review Committee 
An Independent Review Committee (IRC) will be established under the direction of the Sponsor 
to provide an objective, unbiased, independent review of objective response, using the IMWG 
criteria (Table 6), as demonstrated based on the pertinent clinical data from the study. 
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A formal, written IRC charter will be established outlining the composition of the IRC, the data 
to be evaluated, and the manner of committee meetings.  
9.4. 
Pharmacokinetics 
Serial blood samples for PK analysis will be collected after each tinostamustine dose according 
to the schedule in Table 1. Blood samples for PK assessment should be collected following the 
15-minute supine, resting periods described for the continuous Holter recordings. PK samples are 
to be collected from the arm opposite of that used for tinostamustine administration. 
The calendar date and exact 24-hour clock time of blood sample collection for PK assessments 
will be documented in the source document and the eCRF. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.  
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10. 
STATISTICAL ANALYSES 
10.1. 
Statistical Basis for Sample Size 
Across both Phases 1 and 2 of the study, a total of up to ~86 patients may be enrolled. 
A formal sample size determination/power calculation was not performed for the first phase of 
the study. Based on experience from previously published similar studies, a total number of 
9 (minimum) to 12 (maximum) patients in the dose escalation stage of the study are foreseen. 
For Phase 2 of the study, superiority testing will be performed to investigate the null hypothesis 
that the primary endpoint of responder rate is below or equal to the gold standard against the 
alternative hypothesis that it is higher than the gold standard. The gold standard is assumed to be 
77.5% and a one-sided chi-square test will be performed at the 2.5% level of significance. For 
power considerations, the alternative working hypothesis is that the responder rate for the study 
treatment is at least 90%. 
In the methodology proposed by Simon (Simon, 1989), a Phase 2 design can be represented by 
4 numbers: N1, R1, N, and R. N1 is the sample size in the first stage. R1 is the critical value in 
the first stage. If R1 or fewer responses occur in the N1 patients, the study treatment is rejected. 
N is the combined sample size for both the first and second stages. R is the critical value in the 
combined sample. If R or fewer of the N patients respond, the study treatment is rejected at the 
end. 
The design is found with PASS Sample Size Software through an exhaustive search of all 
possible designs (combinations of R1, N1, R and N) that control alpha (0.025) and beta (0.20, 
meaning power is 0.80). With the minimax approach, the design is selected that has the lowest N. 
Per the minimax design, 31 patients are to be enrolled in Stage 1. If >25 of 31 patients (in the 
FAS) in Stage 1 experience a response to treatment, then enrollment will continue into Stage 2, 
with up to 40 patients planned to be enrolled. However, if ≤25 patients in Stage 1 experience a 
response to treatment, no further patients will be enrolled (in the ongoing Stage 2 recruitment). 
Thus, a total of up to 71 patients will be enrolled in Phase 2.  
If the total number of patients who experience a response is ≥62 of 71, then the study is 
considered a success. 
10.2. 
Statistical and Analytical Plan 
An overview of the statistical methodology to be employed is provided in the following 
subsections. Details regarding the statistical methodology will be documented in a formal 
Statistical Analysis Plan (SAP) prior to database lock.  
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10.2.1. 
General Methods 
Statistical analyses will be primarily descriptive in nature. Statistical hypothesis testing is neither 
intended nor appropriate within this context except for the primary endpoint. Confidence 
intervals will be based on asymptotic methods. 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Categorical variables will be summarized showing 
the number and percentage (n, %) of patients within each classification. 
Dependent of the specific analysis, the analysis sets as defined in Section 10.2.2 will be taken 
from the cohort for Phase 1, for Phase 2 (RP2D) or both phases pooled. Unless specified 
otherwise below, this will be further defined in the SAP. 
10.2.2. 
Analysis Populations 
All patients who receive tinostamustine will be included in the safety set.  
All patients in the safety set who had at least one post-ASCT response evaluation will be 
included in the full analysis set (FAS). 
All patients in the FAS with no major protocol deviations will be included in the per-protocol 
(PP) set. 
All patients in the safety set with at least one quantifiable pre-dose and one quantifiable post-
dose PK plasma concentration will be included in the PK set.  
10.2.3. 
Missing Data 
Analyses will be based on observed data only; no data will be imputed. 
10.2.4. 
Disposition of Patients 
Patients who are screened for study entry and do not meet the eligibility criteria will be 
documented. The numbers and proportions of patients who complete the study and who are early 
terminations will be summarized. Reasons for study discontinuation after the start of study 
treatment will be tabulated. 
10.2.5. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized. Data to be tabulated 
will include demographic and baseline characteristics such as sex, age, race, height, weight, and 
body mass index, and MM-specific diagnostic and historical information. Medical history will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA) and raw and coded data 
will be summarized. 
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10.2.6. 
Extent of Exposure 
Descriptive statistics for the percent of expected dose received and the actual dose received will 
be summarized. A tabular summary and listing of drug administration and dose level, and a by-
patient listing of the date and time of each study drug dose and the dose administered also will be 
presented.  
10.2.7. 
Prior and Concomitant Medications 
Tabulations of prior and concomitant medications, coded using the World Health Organization 
Drug Dictionary (WHO-DD), will be produced. All prior and concomitant medications 
administered will be presented in a data listing.  
10.2.8. 
Efficacy Analyses 
Superiority testing will be performed on FAS in the Phase 2 cohort to investigate the null 
hypothesis that the primary endpoint of responder rate is below or equal to the gold standard 
against the alternative hypothesis that it is higher than the gold standard. The gold standard is 
assumed to be 77.5% (CIBMTR report, December 2017) and a 1-sided 2-step chi-square test will 
be performed at the 2.5% level of significance for FAS. 
For the primary endpoint, also an upper 1-sided 97.5% confidence interval will be calculated for 
FAS in addition to summary statistics. 
For the primary endpoint in other sets and for the secondary endpoints of other responder rates in 
the FAS, also 2-sided 95% confidence intervals will be calculated in addition to summary 
statistics.  
Response assessments as determined by the Investigator and IRC will be compared, with 
agreement determined by Kappa coefficient. 
Disease assessment variables and their changes from baseline will be summarized visit wise.   
10.2.9. 
Pharmacokinetic Analyses 
PK analysis for tinostamustine and its metabolites will be performed using the PK set.  
PK parameters at all doses will include Cmax, time to maximum plasma concentration (tmax), t1/2, 
area under the plasma concentration curve from 0 to 12 hours (AUC0-12), area under the plasma 
concentration curve from time 0 to time t (AUC0-t), apparent total clearance (CL/F), apparent 
volume of distribution (Vd/F), and terminal disposition rate constant (λz). The initial calculation 
of PK parameters will be performed using non-compartmental analysis. Plasma concentrations 
and PK parameters will be summarized by dose. 
Summaries will include the number of observations (n), arithmetic or geometric mean, SD or 
coefficient of variation (CoV), median, minimum, and maximum. 
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10.2.10. 
Safety Analyses 
Safety data, including changes from baseline, if applicable, will be summarized at each dose 
level for the safety set. 
Adverse Events will be coded using MedDRA and raw and coded data will be summarized. 
Additional safety analyses may be determined at any time without prejudice, in order to 
enumerate rates of toxicities most clearly, and to define further the safety profile of 
tinostamustine. 
10.2.11. 
Interim Analyses 
In Phase 2 of the study, at the completion of the Stage 1 with 31 patients, an interim analysis will 
be performed using the FAS for the Phase 2 cohort to determine whether enrollment will 
continue in Stage 2. If >25 of 31 patients in Stage 1 experience a response to treatment, then 
enrollment will continue in Stage 2, with up to 40 patients planned to be enrolled. However, if 
≤25 patients in Stage 1 experience a response to treatment, no further patients will be enrolled in 
in the ongoing Stage 2 recruitment.   
10.3. 
Changes to the Planned Statistical Methods 
Changes to the planned statistical methods will be documented in the clinical study report. 
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11. 
ETHICAL, LEGAL, AND ADMINISTRATIVE 
CONSIDERATIONS 
11.1. 
Good Clinical Practice 
This study will be conducted according to the protocol and in compliance with ICH GCP, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory 
requirements. 
The Investigator confirms this by signing the protocol. 
11.2. 
Informed Consent  
Written informed consent will be obtained from each patient prior to undergoing any protocol-
specific tests or procedures that are not part of routine care. 
The Sponsor or designee will provide an ICF template to the Investigator for use in developing a 
study center-specific consent documents. Prior to submission of the study center-specific ICF to 
the IRB/EC, these documents must be reviewed and approved by the Sponsor or designee. Any 
changes requested by the IRB/EC must also be approved by the Sponsor or designee. The final 
IRB/EC-approved ICF must be provided to the Sponsor or designee. Revisions to the ICF 
required during the study must be approved by the Sponsor r designee, and a copy of the revised 
ICF provided to the Sponsor or designee. 
Before recruitment and enrollment, each prospective patient will be given a full explanation of 
the study and be allowed to read the ICF in a language they understand. After the Investigator or 
designee is assured that the patient understands the commitments of participating in the study, 
the patient will be asked to sign and date the ICF, as appropriate.  
A copy of the fully signed and dated ICF will be given to the patient. The original will be 
maintained in the patient’s medical record at the study center. All active patients will sign an 
updated ICF if revisions are made to the ICF during the course of the study. 
11.3. 
Institutional Review Board/Ethics Committee 
Federal and European regulations and ICH require that approval be obtained from an IRB/EC 
prior to participation of patients in research studies. Approval by the Competent Authority, if 
applicable, or as required by local laws and regulations, is also required in Europe. Prior to the 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian, must be approved by the IRB/EC. 
All IRB/EC approvals must be dated and signed by the IRB/EC Chairperson or designee and 
must identify the IRB/EC 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. 
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No drug will be released to the site to dose a patient until written IRB/EC 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/EC. The Investigator must supply the Sponsor or 
designee with written documentation of the approval of the continued clinical research. 
The Investigator, sponsor, or designee as applicable, will make all attempts to ensure that the 
IRB/EC is constituted and operates in accordance with Federal and ICH GCP and any local 
regulations. 
11.4. 
Amending the Protocol 
Any changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor or designee and the IRB/EC that 
approved the study. Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB/EC for approval prior to patients being enrolled into the amended protocol. 
The Sponsor may make administrative changes (i.e., changes that do not significantly affect 
patient safety or the study’s scope or scientific quality) without any further approvals.  
All amendments will be distributed to all protocol recipients. 
11.5. 
Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and other 
study personnel must not disclose such information without prior written approval from the 
Sponsor. 
Patient confidentiality will be strictly maintained to the extent possible under the law. Patient 
names must not be disclosed. Patients will be identified in the eCRFs and other documents 
submitted to the Sponsor or its designated representative, by their initials, birth date, and/or 
assigned patient number. Documents that identify the patient (e.g., the signed ICF) should not to 
be submitted to the Sponsor or its designated representative, and must be maintained in 
confidence by the Investigator. 
11.6. 
Publication Policy 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. The initial planned publication will be 
a multicenter report of the study outcome. Additional publications from a given center can only 
occur after the publication of the multicenter results. A prepublication manuscript is to be 
provided to the Sponsor at least 30 days prior to the submission of the manuscript to a publisher. 
Similarly, the Sponsor will provide any company-prepared manuscript to the Investigators for 
review at least 30 days prior to submission to a publisher.  
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12. 
STUDY MANAGEMENT 
12.1. 
Data Quality Assurance 
The Sponsor or its designated representative will conduct a study center visit to verify the 
qualifications of each investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
12.2. 
Case Report Forms and Source Documentation 
The Investigator and designees agree to maintain accurate eCRFs and source documentation as 
part of case histories. Source documents are the originals of any documents used by the 
Investigator or subinvestigator or hospital/institution that allow verification of the existence of 
the patient and substantiate the integrity of the data collected during the study. 
The Sponsor or designee will provide eCRFs to the study center. eCRFs will be completed for 
each patient. It is the Investigator’s responsibility to ensure the accuracy, completeness, and 
timeliness of the data reported in the patient’s eCRF. Source documentation supporting the eCRF 
data should indicate the patient’s participation in the study and should document the dates and 
details of informed consent, study procedures, AEs, and patient status.  
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected/data are available, preferably on the same day that a patient is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data.  
12.3. 
Monitoring 
A CRA, or other representative of the Sponsor, will conduct a study center visit to verify the 
qualifications of each Investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation.  
During the course of the study, the CRA will make study center visits to review protocol 
compliance, compare eCRFs and individual patients’ medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements in respect to GCP. eCRFs will be verified with source documentation. The review 
of medical records will be performed in a manner to ensure that patient confidentiality is 
maintained. 
12.4. 
Inspections 
Regulatory authorities and/or quality assurance personnel from the Sponsor or its designated 
representative, may wish to carry out such source data checks and/or in-center audit inspections. 
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The Investigator assures the Sponsor of the necessary support at all times. In the event of an 
audit, the Investigator agrees to allow the sponsor’s representatives and any regulatory agencies 
access to all study records.  
12.5. 
Financial Disclosure Reporting Obligations 
Investigators and subinvestigators are required to provide financial disclosure information to the 
sponsor to permit the sponsor to fulfill its regulatory obligation. Investigators and 
subinvestigators must commit to promptly updating the information if any relevant changes 
occur during the study and for a period of 1 year after the completion of the study. 
12.6. 
Archiving Study Records 
Essential documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. However, these documents should be 
retained for a longer period if required by the applicable local requirements. 
ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
 
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13. 
REFERENCES 
Ahn C. An evaluation of phase I cancer clinical trial designs. Stat Med 1998;17(14):1537-49. 
Barba P, Piñana JL, Martino R, Valcárcel D, Amorós A, Sureda A, et al. Comparison of two 
pretransplant predictive models and a flexible HCT-CI using different cut points to determine 
low-, intermediate-, and high- risk groups: the flexible HCT-CI is the best predictor of NRM and 
OS in a population of patients undergoing allo-RIC. Biol Blood Marrow Transplant 
2010;16:413-420.  
Batlle M, Morgades M, Vives S, Ferrà C, Oriol A, Sancho JM, et al. Usefulness and safety of 
oral cryotherapy in the prevention of oral mucositis after conditioning regimens with high-dose 
melphalan for autologous stem cell transplantation for lymphoma and myeloma. Eur J Haematol. 
2014;93(6):487-91. 
Bayraktar UD, Bashir Q, Qazilbash M, Champlin RE, Ciurea SO. Fifty years of melphalan use in 
hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013;19(3):344-56.  
Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, et al. A 
randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients 
with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant 2016;51(1):67-71. 
Dillman RO, Koziol JA. Phase I cancer trials: limitations and implications. Mol Biother 
1992;4(3):117-21. 
Farina L, Bruno B, Patriarca F, Spina F, Sorasio R, Morelli M, et al. The hematopoietic cell 
transplantation comorbidity index (HCT-CI) predicts clinical outcomes in lymphoma and 
myeloma patients after reduced- intensity or non-myeloablative allogeneic stem cell 
transplantation. Leukemia 2009;23:1131-1138.  
Garderet L, D'Souza A, Jacobs P, van Biezen A, Schönland S, Kroeger N, et al. Response 
assessment in myeloma: practical manual on consistent reporting in an era of dramatic 
therapeutic advances. Biol Blood Marrow Transplant. 2017;23(7):1193-1202.  
Gatsonis C, Greenhouse JB. Bayesian methods for phase I clinical trials. Stat Med 
1992;11(10):1377-89. 
Gonsalves WI, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, et al. Second auto-
SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant 2013;48(4):568-73. 
Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one 
size does not fit all. Blood 2014;124(3):344-353. 
International Council for Harmonisation. E8:  General Considerations of for Clinical Trials, July 
1997. 
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Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J, et al. Autologous stem cell 
transplantation: an effective salvage therapy in multiple myeloma. Biol Blood Marrow 
Transplant 2013 Mar;19(3):445-9. 
Maruyama D, Fukuda T, Kato R, Yamasaki S, Usui E, Morita-Hoshi Y, et al. Comparable 
antileukemia/lymphoma effects in nonremission patients undergoing allogeneic hematopoietic 
cell transplantation with a conventional cytoreductive or reduced- intensity regimen. Blood 
Marrow Transplant 2007;13:932-941.  
Maybury B, Cook G, Pratt G, Yong K, Ramasamy K. Augmenting Autologous Stem Cell 
Transplantation to Improve Outcomes in Myeloma. Biol Blood Marrow Transplant 
2016;22(11):1926-1937.  
McCarthy PL, Hahn T. Strategies for induction, autologous hematopoietic stem cell 
transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma 
patients. Hematology Am Soc Hematol Educ Program 2013;2013:496-503. 
Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI, et al. Salvage second 
hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant 2013;19(5):760-6.  
Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body 
irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell 
transplantation in patients with newly diagnosed multiple myeloma: final analysis of the 
Intergroupe Francophone du Myélome 9502 randomized trial. Blood 2002;99:731-735 
Musso M, Messina G, Marcacci G, Crescimanno A, Console G, Donnarumma D, et al. High-
Dose melphalan plus thiotepa as conditioning regimen before second autologous stem cell 
transplantation for “de novo” multiple myeloma patients: a phase II study. Biol Blood Marrow 
Transplant 2015;21:1932e1938. 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:  
Multiple Myeloma, Version 3.2018, November 22, 2017. Available at:  
https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed:  29 November, 2017. 
Reece D, Song K, LeBlanc R, Mezzi K, Olujohungbe A, White D, et al. Efficacy and safety of 
busulfan-based conditioning regimens for multiple myeloma. Oncologist 2013;18(5):611-8. 
Simon R. Optimal two-stage deigns for phase II clinical trials. Controlled Clinical Trials 
1989;10:1-10. 
Sorror ML, Giralt S, Sandmaier BM, de Lima M, Shahjahan M, Maloney DG, et al. 
Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for 
patients with acute myeloid leukemia in first remission: Combined FHCRC and MDACC 
experiences. Blood 2007;110:4608-4613.  
Storer BE. Design and analysis of phase I clinical trials. Biometrics 1989;45(3):925-37. 
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Date: September 21, 2018 
To: EDO-S101-1004 (TITANIUM 1) Investigators and Site Staff 
Protocol Title: A Phase 1/2 Open-Label Trial of Tinostamustine Conditioning and Autologous Stem Cell 
Transplant for Salvage Treatment in Relapsed/Refractory Multiple Myeloma (TITANIUM 1) 
Protocol Version: 2.0, 18 June 2018 
Subject: Protocol Clarification Memo 
Dear Investigators and Site Staff, 
Please see below clarifications for EDO-S101-1004 version 2.0 protocol from 18 June 2018. 
Item 1: Use of central line 
Currently, Protocol Version 2.0 18 June 2018 states on the bottom of page 11, that Tinostamustine will 
be administered by IV infusion through a peripheral vein over 1 hour. This is also noted in section 7.6.2 
on page 49. 
It should say that Tinostamustine will be administered by IV infusion through a peripheral vein or a 
central line over 1 hour. 
Item 2: Day of Autologous Stem Cell Transplant (ASCT) 
Currently, Protocol Version 2.0 18 June 2018 states in the header of the Schedule of Events on pages 17 
and 18, that ASCT is on Day 0. 
It should say that the day of ASCT is study Day 1. 
Item 3: Exclusion Criteria #2 
li Page 
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Currently, Protocol Version 2.0 18 June 2018 has two Exclusion Criteria #2's listed on page 39. The one 
noted as "Primary or secondary plasma cell leukemia at any point prior to transplant" is not noted in the 
Clinical Study Synopsis exclusion criteria list on page 10. 
This exclusion criteria should be included in the Clinical Study Synopsis. 
Item 4 Protocol Deviations 
Currently, Protocol Version 2.0 18 June 2018 states that all protocol deviations and reasons for such 
deviations must be noted in the eCRF. 
It should say that all protocol deviations and reasons for such deviations must be noted in the CTMS. 
Item 5 Confirmatory Response Assessment 
Currently, Protocol Version 2.0 18 June 2018 states on pages 12 and 42 that a confirmatory response 
assessment will be done between D107 and D130. On the schedule of assessments on pages 17 and 18, 
it is listed as D130 (+/-7 days). 
It should say that a confirmatory response assessment will be done between D107 and D130, ideally 
approximately 4 weeks after the initial evaluation. 
Item 6 Discharge Criteria 
Currently/ Protocol Version 2.0 18 June 2018 states on pages 6 and 37 that the following engraftment 
criteria need to be met in order for the patient to be discharged: 
• 
Neutrophil engraftment is defined as the first of 3 consecutive days with ANC >O.Sx109/L. 
• 
Platelet engraftment will be defined as the first 3 consecutive days of platelet count >20x109/l 
without platelet transfusion in the prior 7 days. 
It should say the following: 
• 
Absolute neutrophil count >O.Sx109/L. 
• 
Patient is not platelet transfusion dependent. 
Item 7 Triplicate ECGs 
Currently, Protocol Version 2.0 18 June 2018 states on footnote 9 of the schedule of assessments on 
page 19 that triplicate ECGs should be separated by 5 minutes (+/-2 minutes). 
It should say that triplicate ECGs should be at least 1 minute apart. 
Item 8 Fractionated Creatinine 
21 Page 
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PPD


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D


EDO 
-
GmbH 
Date: 14 December 2018 
To: EDO-S101-1004 (TITANIUM 1) Investigator and Site Staff 
Protocol Title: A Phase 1/Z Open-Label Trial of Tinostamustine Conditioning and Autologous 
Stem Cell Transplantation for Salvage Treatment in Relapsed/Refractory Multiple Myeloma 
(TITANIUM 1) 
Protocol Version: 2.0, 18 June 2018 
Subject: Protocol Clarification Memo 
Dear Investigator and Site Staff, 
Please see below clarifications for EDO-S101-1004 version 2.0 protocol18 June 2018. An 
amendment is forthcoming with these changes incorporated. 
Item 1: Evaluation of PKs as an Endpoint, Synopsis Pgs. 3-4; Section 3.1.1.2 & 3.1.2.2, Section 
3.2 
Synopsis pages 3-5 and Section 3.1.1.2 lists "Investigate the pharmacokinetics (PK) of 
Tlnostamustine" as a secondary objective of the phase I portion of the trial. Synopsis pages 
3-5 Section 3.1.2.2 lists "Evaluate the PK of Tlnostamustine" as a secondary objective of the 
phase II portion of the trial. 
Synopsis pages 3-5 and protocol section 3.2 will be updated to reflect a third endpoint in the 
new section "3.2.3 Pharmacokinetics (PK)", with the description "Evaluate and investigate 
the pharmacokinetics (PK) of Tinostamustine". 
Item 2: Exclusion of Hypersensitivity to IMP, Synopsis Pg.11; Section 5.2 
Currently, Protocol Version 2.0 18 June 2018 does not include hypersensitivity to IMP as an 
exclusion criterion. The following protocol exclusion criteria will be updated to include the 
following text to the above sections. 
13. Subjects who are known to have any hypersensitivities or allergies to any ingredient of 
the investigational agent are not eligible to participate. 
Item 3: Infections Diseases Exclusion, Synopsis Pg.11; Section 5.2 
Currently, Protocol Version 2.0 18 June 2018 does not include exclusion criterion regarding 
positive serology on any of the disease screened for as described in section 9.1 .8 (pg. 55). The 
following protocol exclusion criteria will be updated to include the following text to the 
above sections. 
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14. Subjects who are known to have or test positive for human immunodeficiency virus (HIV) 
types 1 and 2, hepatitis 8 virus (HBV) panel (HBV surface antigen, HBV surface antibody, HBV 
core antibody, HBV e-antigen), hepatitis C virus (HCV), Treponema pallidum, 
cytomegalovirus, and Epstein-Barr virus, may not participate in this study. 
Item 4: Definition of People of Childbearing Potential, Section 5 "Study Population" New Sub-
Section 
Currently, Protocol Version 2.0 18 June 2018 does not define women or men of childbearing 
potential. The protocol will be amended to include the following text: 
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medkal 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. A man is considered fertile after puberty unless 
permanently sterile by bilateral orchidectomy. 
Item 5: Acceptable methods of highly effective contraception, Section 5 "Study Population" 
New Sub-Section 
Currently, Protocol Version 2.0 18 June 2018 does not list acceptable methods of effective 
contraception. The protocol will be amended to include the following text: 
Methods that achieve a failure rate of less than 1% per year when consistently and correctly 
used are considered highly effective methods of birth control. Highly effective methods of 
birth control include: estrogen and progestogen combined hormonal contraception whkh 
inhibits ovulation, progestogen-only hormonal contraception associated with inhibition of 
ovulation, intrauterine devices (IUD), bilateral tubal occulusion, vasectomized partner in a 
monogamous sexual relationship, and complete sexual abstinence. Acceptable, but less 
effective (>1% failure rate per year) methods such as male or female condom with 
spermicide, cap, diaphragm, or sponge with spermicide, or double barrier methods may be 
used in conjunction with another form of highly effective birth control. 
Item 6: Duration of contraception requirement, Section 5 "Study Population" New Sub-
Section 
Currently, Protocol Version 2.0 18 June 2018 does not provide a proposed duration for the 
contraception requirement. The protocol will be amended to include the following text: 
Males and females of child bearing potential, and their partners, must be willing to use at 
least two effective forms of birth control for at least ninety (90) days after the 
administration of the study drug to be eligible to participate. These requirements were 
created based on the recommendations by the Clinical Trial Faciliation Group (CTFG) 
"Recommendations related to contraception and pregnancy testing in clinical 
trials" (15Sep2014) due to the alkylating nature of the drug and the limited data on 
genetotoxici ty. 
Item 7: Contraception Eligibility, Synopsis Pg.10; Pg. 39 Section 5.1 
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Currently, Protocol Version 2.0 18 June 2018 does not include guidance on pregnancy 
contraception and eligibility. The following protocol inclusion criteria will be updated to 
include the following text to the above sections. 
12. Males and females of child bearing potential, and their partners, must be willing to use 
at least two effective forms of birth control for at least ninety (90) days after the 
administration of the study drug to be eligible to participate. 
Item 8: Exclusion criteria #9, Synopsis Pg.11; Pg. 39 Section 5.2 
Currently, Protocol Version 2.0 18 June 2018 states that patients who are found to be 
pregnant, are not eligible. Current exclusion criteria number 9 will be updated with the 
below language. 
9. Women who are pregnant or breastfeeding, or plan to become pregnant or breastfeed, are 
not eligible for study participation. 
Item 9: End of trial definition, Synopsis Pg.12 
Currently, Protocol Version 2.0 18 June 2018 does not contain a clear and unambiguous 
definition of end of trial. In the protocol synopsis (Pg. 12) under "Duration of Treatment and 
Study Duration" the following text will be added: The end of trial will be the last patient last 
visit (LPLV). 
Item: 1 0: Summary of known and potential risks and benefits to human subjects 
Currently, Protocol Version 2.0 18 June 2018 does not include a summary of known and 
potential risks and benefits to human subjects. The following text will be added in a protocol 
amendment as new section 4.3 "Risks and Benefits, in the protocol: 
This study is investigating the use of Tinostamustine 
On the sister study, Tinostamustine is being tested the first in human study in patients with 
relapsed or refractory haematological malignancies for which there are no available 
approved therapies. Preliminary signals show that the treatment with tinostamustine may 
offer benefit by overcoming tumor resistance and trigger response. As a result, this therapy 
may slow down or stop disease progression. Out of 37 patients evaluable for efficacy during 
the dose-escalation part of the study, approximately half have benefited from treatment. 
The risks associated with the treatment with tinostamustine are expected to be similar to 
other alkylators, like bendamustine. The peripheral cell compartments show a differential 
sensitivity to tinostamustine, with lymphocytes being most sensitive and platelets most 
robust, but showing the most rapid decline at higher doses. Due to myelosuppression, 
patients may be more susceptible to infections. The analysis of the chemistry data showed 
no other meaningful or serious organ toxicity. ECGs during and after infusion showed small 
prolongations of the QTc interval during and post infusion. Mean change from baseline were 
up to 24 ms and were clinically not significant. Blood pressure and heart frequency showed 
no notable changes in any subjects at any dose levels. Patients may experience various types 
of gastrointestinal toxicity such as nausea, vomiting or diarrhea. At the studied doses these 
events were non-severe. Mundipharma-EDO considers the benefit and risk balance to be in 
favour of further development of this molecule in humans. 
Possible Risks Include: 
• 
Myelosuppression (thrombocytopenia, leukopenia, and neutropenia) 
• 
Anemia 
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• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation) 
Cough 
Peripheral edema 
Pyrexia 
Decreased appetite 
Dyspnea 
Headache 
Asthenias 
Allergic reaction 
Infection 
QTc Prolongation 
As noted above, the risks associated with the treatment with Tinostamustine are expected to 
be similar to other alkylators, like bendamustine. Additionally, patients undergoing any high-
dose conditioning for transplant, will experience myelosuppression, which puts the patients 
at a higher risk for infection. Thus, the protocol was designed around current standard 
practices for monitoring the toxicity and safety of patients in this treatment setting. 
Patients are evaluated daily for hematologic parameters, signs of infection, and any other 
adverse reactions until engraftment is reached. After engraftment the patients are 
monitored monthly through 130 days but may be seen in between these timepoints if 
clinically indicated. Cardiac safety is monitored pre-infusion through 24 hours post infusion 
with a continuous hotter monitor, in addition to ECGs being performed and read by the 
qualified site personnel before, during, and after the infusion. Other adverse reactions will 
be continuously monitored and treated as appropriate according to the protocol and local 
standard of care. 
Since the purpose of this study is to evaluate the safety and preliminary efficacy of this 
regimen, it is unknown if this treatment will benefit individual patients directly. While the 
study may or may not improve the disease of the patients, they could benefit in the 
following ways: 
• 
• 
Helping others by contributing to medical research 
Monitoring of their condition while on the study with additional study services and 
evaluations. 
While this investigational agent and regimen are being studied, the ongoing sister studies 
have shown some early promising results. Preliminary data shows that treatment with this 
agent may offer benefit by overcoming tumor resistance and trigger response. As a result, 
this therapy may slow down or stop disease progression. Therefore, Mundipharma-EDO 
considers the benefit and risk balance to be in favour of further development of this 
molecule in humans. 
Item 11: Very good partial response (VGPR), Synopsis Pg.4; Pg. 34 Section 3.2.1.1 
Currently, Protocol Version 2.0 18 June 2018 does not include in the main body of the protocol 
(Pg. 34 Section 3.2.1.1) VGPR as a type of ORR, while the Synopsis on pg. 4 does list VGPR as 
a type of ORR. The main body of the protocol will be updated to add "Very Good Partial 
Response (VGPR)" in section 3.2.1.1. 
Item 12: Inclusion criteria #2, Synopsis Pg. 9; Pg. 38 Section 5.1 
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Date: January 30, 2019 
To: EDO-S101-1004 (TITANIUM 1) Investigators and Site Staff 
Protocol Title: A Phase 112 Open-Label Trial of Tinostamustine Conditioning and Autologous 
Stem Cell Transplant for Salvage Treatment in Relapsed/Refractory Multiple Myeloma 
(TITANIUM 1) 
Protocol Version: 2.0, 18 June 2018 
Subject: Protocol Clarification Memo 
Dear Investigators and Site Staff, 
The purpose of this memo is to provide a list of recommended anti -emetic medications, to 
clarify performance of the bone marrow MRD assessment at day 100, and to clarify screening 
serology results. An amendment is forthcoming with these changes incorporated. 
Recommended Anti -Emetics 
Due to its association with QTc prolongation, ondansetron is prohibited around the time of 
tinostamustine dosing. Also, due to reported interactions with alkylating agents, aprepitant is 
also not allowed for nausea control. We, therefore, recommend the following anti-emetic 
medications for nausea control on day -1: 
• 
• 
• 
• 
Palonosetron 
Glucocortcoids-as single agent or in combination with palonosetron 
Olanzapine 
Lorazepam-in combination with other recommended anti-emetics 
Given the short half-life of tinostamustine, ondansetron can be used up to 24 hours prior to 
tinostamustine dosing on day -1 and resumed 24 hours after the dose. In patients with mild 
hepatic dysfunction, this interval should be extended to 48 hours due to reports of delayed 
clearance of ondansetron in this population. Since aprepitant has a long half-life, it should 
not be administered at least 3 days prior to tinostamustine dosing. If needed, aprepitant can 
be given 24 hours after tinostamustine dosing. 
Bone Marrow: Day 100 Assessment, in Phase 2 only 
At day 100, subjects who meet laboratory criteria for CR only will undergo a bone marrow 
assessment. Samples will be obtained for pathology examination and MRD-N analysis. 
1 I Page 
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SAP_001.pdf: 
16.1.9 
Documentation of statistical methods 
• Statistical Analysis Plan - Version 1.0 
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13 May 2020
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3
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Protocol No. EDO-S101-1004
13 May 2020
15
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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
16
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CCI
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Mundipharma-EDO GmbH
Version No. Final
Protocol No. EDO-S101-1004
13 May 2020
17
CCI
CCI
CCI