Tinostamustine Conditioning and Autologous Stem Cell | NCT03687125

ID	Type	Description	Link
2018-001907-35	EudraCT Number

Status Module

Description Module

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.

Label	Type	Description	Intervention Names
Tinostamustine 180 mg/m^2	Experimental	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.	Drug: Tinostamustine Procedure: Autologous Stem Cell Transplant (ASCT)
Tinostamustine 220 mg/m^2	Experimental	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.	Drug: Tinostamustine Procedure: Autologous Stem Cell Transplant (ASCT)

Name	Type	Description	Arm Group Labels	Other Names
Tinostamustine	Drug	Participants received tinostamustine IV injection.	Tinostamustine 180 mg/m^2 Tinostamustine 220 mg/m^2

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase 2: Objective Response Rate (ORR) Based on International Myeloma Working Group (IMWG) Response Criteria	ORR was defined as the participants with a complete response (CR) or very good partial response (VGPR) or partial response (PR) as determined by IMWG Response Criteria. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to less than (<) 10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum longest diameter; VGPR was defined as a >90% reduction in serum IgM levels from baseline.	at Day 100 post-autologous stem cell transplant (ASCT)
Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)	DLT was defined as at least possibly related to tinostamustine based on common terminology criteria for adverse events 4.03 (CTCAE 4.03): (1) delayed engraftment (greater than [>] 30 days after ASCT) where subject has not met criteria for both neutrophil (first of 3 consecutive days with ANC > 0.5×10^9/liter [L]) and platelet (plt) engraftment (first of 3 consecutive days of plt count > 20×10^9/L without plt transfusion in prior 7 days) (2) QTcF > 500 millisecond (msec) or > 60 msec increase from baseline with duration of > 30 minutes or greater than or equal to (>=) Grade 3 QTcF interval prolongation with ventricular arrhythmia (3) Grade 4 non-hematologic toxicity (4) Grade 3 non-hematologic toxicity related to treatment, except: nausea, emesis, diarrhea, fatigue, dehydration, glucose intolerance, skin rash with treatment, fever (> 40C for >= 24 hours), infection, dyspnea, hypoxia, pneumonitis, pain, dysphagia, oral mucositis, anorexia, flu-like or engraftment syndrome, weight.	Phase 1: From Day -1 up to 30 Days post-ASCT

Secondary Outcomes

Measure	Description	Time Frame
Phase 1 and 2: Objective Response Rate (ORR) for Participants Treated at the Recommended Phase 2 Dose (RP2D)	ORR for participants who achieved CR, minimal residual disease negativity (MRD-N), was determined by next generation flow cytometry according to the IMWG Criteria.	at Day 100 post ASCT
Phase 1 and 2: Number of Participants With Neutrophil and Platelet Engraftment Failure

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Participants has Multiple Myeloma (MM) and:

a. Has received prior ASCT after standard first-line induction treatment. b. Has evidence of progressive disease (PD), with progression-free interval greater than or equal to (>=) 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 lesser than or equal to (<=) 3 prior lines of therapy.
- A line of therapy is defined as 1 or more cycles of a planned treatment program. When participants have undergone sequential phases of treatment without intervening progression, such as induction, collection of peripheral blood stem cells (PBSCs), 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.
Complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to salvage chemotherapy, as determined by the International Myeloma Working Group (IMWG) criteria.
Is, in the Investigator's opinion, a candidate for consolidation therapy with tinostamustine followed by ASCT. (Note that participants planned to receive tandem ASCT are not eligible for the Phase 1 portion of the study.)
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 participant with a large number of available PBSCs to permit subsequent ASCT, as participants in Stage 1 may received a dose lower than that determined to be effective.)
Age 18-75 years.
Eastern Cooperative Oncology Group (ECOG) performance status score lesser than (<) 3 at Screening.
Creatinine clearance >= 40 milliliter per minute (mL/min), as determined by a local laboratory using the Cockcroft-Gault equation within 28 days before ASCT.
Left ventricular ejection fraction (LVEF) >= 40 percent (%) within 28 days before ASCT.
Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) greater than (>) 50% predicted within 28 days before ASCT.
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.
Potassium within the local laboratory's normal range. (Potassium supplementation is permissible.)

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for study entry:

History of central nervous system (CNS) disease involvement.
Primary or secondary plasma cell leukemia at any time point prior to transplant.
Myocardial infarction (MI) or stroke within 6 months before Screening.
Uncontrolled acute infection.
Hematopoietic cell transplantation-comorbidity index (HCT-CI) > 6 points.
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.
Major coagulopathy or bleeding disorder.
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.
Lack of cooperation to allow study treatment as outlined in this protocol.
Pregnancy or lactating female participants.
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.
Receiving treatment with drugs known to prolong the QT/QTc interval.
QTc interval (Fridericia's formula) > 450 millisecond (msec), based on the mean of triplicate Screening 12-lead electrocardiograms (ECGs).

Name	Affiliation	Role
Parameswaran Hari, MD	Study Chair	Study Chair
Dagmar Hess	2nd Study Chair	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
University of Alabama		Birmingham	Alabama	35294	United States
University of Kansas Medical Center Kansas City

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Tinostamustine 180 mg/m^2	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.
FG001	Tinostamustine 220 mg/m^2

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 18, 2018	Apr 1, 2021

ID	Title	Description
BG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
BG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection followed by ASCT on Day 1.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0003 BG0013 BG0026

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Phase 2: Objective Response Rate (ORR) Based on International Myeloma Working Group (IMWG) Response Criteria

ORR was defined as the participants with a complete response (CR) or very good partial response (VGPR) or partial response (PR) as determined by IMWG Response Criteria. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to less than (<) 10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum longest diameter; VGPR was defined as a >90% reduction in serum IgM levels from baseline.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1, participants were not enrolled in Phase 2. Hence, no efficacy analysis were analyzed or collected in this study.

Posted

at Day 100 post-autologous stem cell transplant (ASCT)

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG0000 OG0010

Primary

Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)

DLT was defined as at least possibly related to tinostamustine based on common terminology criteria for adverse events 4.03 (CTCAE 4.03): (1) delayed engraftment (greater than [>] 30 days after ASCT) where subject has not met criteria for both neutrophil (first of 3 consecutive days with ANC > 0.5×10^9/liter [L]) and platelet (plt) engraftment (first of 3 consecutive days of plt count > 20×10^9/L without plt transfusion in prior 7 days) (2) QTcF > 500 millisecond (msec) or > 60 msec increase from baseline with duration of > 30 minutes or greater than or equal to (>=) Grade 3 QTcF interval prolongation with ventricular arrhythmia (3) Grade 4 non-hematologic toxicity (4) Grade 3 non-hematologic toxicity related to treatment, except: nausea, emesis, diarrhea, fatigue, dehydration, glucose intolerance, skin rash with treatment, fever (> 40C for >= 24 hours), infection, dyspnea, hypoxia, pneumonitis, pain, dysphagia, oral mucositis, anorexia, flu-like or engraftment syndrome, weight.

Posted

Count of Participants

Participants

Phase 1: From Day -1 up to 30 Days post-ASCT

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2

Secondary

Phase 1 and 2: Objective Response Rate (ORR) for Participants Treated at the Recommended Phase 2 Dose (RP2D)

ORR for participants who achieved CR, minimal residual disease negativity (MRD-N), was determined by next generation flow cytometry according to the IMWG Criteria.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1, participants were not enrolled in Phase 2. Hence, no efficacy analysis were analyzed or collected in this study.

Posted

at Day 100 post ASCT

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG000

Secondary

Phase 1 and 2: Number of Participants With Neutrophil and Platelet Engraftment Failure

Neutrophil engraftment was defined as the first of 3 consecutive days with absolute neutrophil count (ANC) >0.5 × 10 ^9/L. Platelet engraftment was defined as the first of 3 consecutive days of platelet count >20 × 10 ^9/L without platelet transfusion in the prior 7 days. Number of participants with neutrophil and platelet engraftment failure was reported.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1. Hence, data for this outcome measure was not collected as planned, analyzed and reported at specific time point.

Posted

up to 6 months

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Duration of Cytopenia

Duration of cytopenia i.e ANC <= 0.5×10^9/L, and platelet count <= 20×10^9/L.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1. Hence, data for this outcome measure was not collected as planned, analyzed and reported at specific time point.

Posted

Up to 6 months

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG000

Secondary

Phase 1 and 2: Number of Participants With Treatment Related Mortality (TRM)

Number of participants with treatment related mortality was reported.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1. Hence, data for this outcome measure was not collected as planned, analyzed and reported at specific time point.

Posted

Up to 6 months

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG000

Secondary

Phase 1 and 2: Number of Participants With Transplant-related Non-hematologic Grade 3 Toxicity

Transplant-related non-hematologic grade 3 toxicity was defined by CTCAE 4.03 stratified by hematopoietic cell transplantation comorbidity index (HCT-CI). HCT-CI is a validated comorbidity index that comprises 17 different categories of organ dysfunction. 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 stem cell transplantation (SCT).

The study was early terminated on 17 April 2019, due to safety signals during Phase 1. Hence, data for this outcome measure was not collected as planned, analyzed and reported at specific time point.

Posted

Up to 6 months

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Serious adverse event (SAE) was defined as AE resulting in any of the following outcomes deemed significant for any other reason: death, was life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as an adverse event that started on or after the first dose of tinostamustine through Day 107, or after the end of the study if thought to be related to study drug.

Posted

Count of Participants

Participants

From first dose of tinostamustine up to end of study (up to 6 months)

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
OG001	Tinostamustine 220 mg/m^2

Secondary

Phase 1 and 2: Change From Baseline in Hematology Parameters

Hematology parameters assessment included white blood cell (WBC) count and differential (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) count, hematocrit, hemoglobin, and platelet count. Change From baseline in hematology parameters at Day 30 were reported.

The study was early terminated on 17 April 2019, due to safety signals during Phase 1. Hence, data for this outcome measure was not collected as planned, analyzed and reported at specific time point.

Posted

Baseline (Day -1), Day 30

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG000

Secondary

Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Electrolytes

Clinical serum chemistry tests included electrolytes i.e. bicarbonate, calcium, magnesium, chloride, glucose, phosphate, potassium, and sodium. Change from baseline in clinical serum chemistry tests i.e. electrolytes at Day 100 were reported.

Posted

Mean

Standard Deviation

millimoles per liter (mmol/L)

Baseline (Day -1), Day 100

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Liver Function Parameters

Clinical serum chemistry tests included liver function parameters i.e. Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Aspartate aminotransferase, (AST) and Lactate dehydrogenase. Change from baseline in clinical serum chemistry tests i.e. liver function parameters at Day 100 were reported.

Safety population included all participants who received tinostamustine. The study was early terminated on 17 April 2019, due to safety signals during Phase 1, participants were not enrolled in Phase 2. Here, number analyzed refers to the number of participants with available data for each specified category.

Posted

Mean

Standard Deviation

units per liter (U/L)

Baseline (Day -1), Day 100

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts

Secondary

Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Renal Function Parameters

Clinical serum chemistry tests included renal function parameters i.e. creatinine and bilirubin. Change from baseline in clinical serum chemistry tests i.e. renal function parameters at Day 100 were reported.

Posted

Mean

Standard Deviation

millimoles per liter (mmol/L)

Baseline (Day -1), Day 100

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Total Protein

Clinical serum chemistry tests included total protein. Change from baseline in clinical serum chemistry tests i.e. total protein at Day 100 were reported.

Posted

Mean

Standard Deviation

gram per liter (g/L)

Baseline (Day -1), Day 100

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.

Units	Counts
Participants	OG000

Secondary

Phase 1 and 2: Time to Reach Maximum Plasma Concentration (Tmax) of Tinostamustine and Its Metabolites

Tmax was defined as time to reach maximum plasma concentration. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.

Pharmacokinetic (PK) population included all participants in the safety population with at least one quantifiable pre-dose and one quantifiable post-dose PK plasma concentration. The study was early terminated on 17 April 2019, due to safety signals during Phase 1, participants were not enrolled in Phase 2.

Posted

Median

Full Range

hours

Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Tinostamustine and Its Metabolites

Cmax was defined as maximum observed plasma concentration. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.

PK population included all participants in the safety population with at least one quantifiable pre-dose and one quantifiable post-dose PK plasma concentration. The study was early terminated on 17 April 2019, due to safety signals during Phase 1, participants were not enrolled in Phase 2.

Posted

Mean

Standard Deviation

nanogram per milliliter (ng/mL)

Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection followed by ASCT on Day 1.

Units	Counts
Participants

Secondary

Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Tinostamustine and Its Metabolites

AUC0-t was defined as area under the concentration-time curve from time zero to the last measurable concentration. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.

Posted

Mean

Standard Deviation

hour*nanogram per milliliter (h*ng/mL)

Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection followed by ASCT on Day 1.

Secondary

Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of Tinostamustine and Its Metabolites

AUC0-12h was defined as area under the concentration-time curve from time zero to 12 hours. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.

Posted

Mean

Standard Deviation

h*ng/mL

Pre-infusion, 0.50, 0.75, 1, 3, 6 hours post-infusion

ID	Title	Description
OG000	Tinostamustine 180 mg/m^2	Participants received single dose of tinostamustine 180 mg/m^2 IV injection followed by autologous stem cell transplantation (ASCT) on Day 1.
OG001	Tinostamustine 220 mg/m^2	Participants received single dose of tinostamustine 220 mg/m^2 IV injection followed by ASCT on Day 1.

Units	Counts

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0012 affected3 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0012 affected3 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Nausea	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0012 affected3 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0011 affected3 at risk
Constipation	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0010 affected3 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Anal incontinence	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Fatigue	General disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Pneumonia	Infections and infestations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Fall	Injury, poisoning and procedural complications	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Patella fracture	Injury, poisoning and procedural complications	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0013 affected3 at risk
Lymphocyte count decreased	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Platelet count decreased	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Blood creatinine increased	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Blood lactate dehydrogenase increased	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Neutrophil count decreased	Investigations	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0012 affected3 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0011 affected3 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0012 affected3 at risk
Acidosis	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Hyperuricaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Spinal pain	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Headache	Nervous system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Paraesthesia	Nervous system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Restless legs syndrome	Nervous system disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Thrombosis in device	Product Issues	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Anxiety	Psychiatric disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Confusional state	Psychiatric disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Insomnia	Psychiatric disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Haematuria	Renal and urinary disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0012 affected3 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Nasal dryness	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk
Hypotension	Vascular disorders	MedDRA (21.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0012 affected3 at risk
Deep vein thrombosis	Vascular disorders	MedDRA (21.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Tinostamustine (180 mg/m^2)	Participants received single dose of 180 mg/m^2 tinostamustine IV injection on Day -1 followed by ASCT on Day 1.	0	3	1	3	3	3
EG001	Tinostamustine (220 mg/m^2)	Participants received single dose of 220 mg/m^2 tinostamustine IV injection on Day -1 followed by ASCT on Day 1.	0	3	2	3	3	3