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NCT03687125: TITANIUM1

Tinostamustine Conditioning and Autologous Stem Cell

Terminated Phase 1, PHASE2 Results posted Last updated 18 June 2021
What this trial tests

Phase 1, PHASE2 trial testing Tinostamustine in Multiple Myeloma in Relapse in 6 participants. Terminated before completion.

Timeline
15 October 2018
Primary endpoint
17 April 2019
17 April 2019

Quick facts

Lead sponsorMundipharma-EDO GmbH
PhasePhase 1, PHASE2
StatusTerminated
Study typeINTERVENTIONAL
Allocationnon randomized
Designsequential
Maskingnone
Primary purposetreatment
Enrollment6
Start date15 October 2018
Primary completion17 April 2019
Estimated completion17 April 2019
Sites12 locations across Switzerland, United States, Norway

Drugs / interventions tested

Conditions studied

Sponsor

Mundipharma-EDO GmbH

Who can join

Adults 18 to 75, any sex, with Multiple Myeloma in Relapse or Multiple Myeloma Progression. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 1: Number of Participants With Dose Limiting Toxicities (DLT) Primary · Phase 1: From Day -1 up to 30 Days post-ASCT

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

GroupValue95% CI
Tinostamustine 180 mg/m^20
Tinostamustine 220 mg/m^20
Phase 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Secondary · From first dose of tinostamustine up to end of study (up to 6 months)

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 hospitalizati

Participants with TEAEs
GroupValue95% CI
Tinostamustine 180 mg/m^23
Tinostamustine 220 mg/m^23
Participants with TESAEs
GroupValue95% CI
Tinostamustine 180 mg/m^21
Tinostamustine 220 mg/m^22
Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Electrolytes Secondary · Baseline (Day -1), Day 100

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.

Bicarbonate: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-0.3± 1.53
Tinostamustine 220 mg/m^2-0.7± 1.15
Calcium: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^20.0667± 0.12332
Tinostamustine 220 mg/m^20.1167± 0.07638
Chloride: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-2.3± 4.04
Tinostamustine 220 mg/m^2-0.3± 1.53
Glucose: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-3.3121± 4.01991
Tinostamustine 220 mg/m^2-0.7771± 2.69209
Magnesium: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-0.0274± 0.09501
Tinostamustine 220 mg/m^2-0.0274± 0.04750
Phosphate: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-0.0969± 0.26439
Tinostamustine 220 mg/m^2-0.2046± 0.29308
Potassium: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^20.20± 0.265
Tinostamustine 220 mg/m^20.10± 0.361
Sodium: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-2.0± 3.61
Tinostamustine 220 mg/m^2-1.3± 1.15
Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Liver Function Parameters Secondary · Baseline (Day -1), Day 100

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.

ALT: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^24.0± 1.73
Tinostamustine 220 mg/m^20.3± 3.06
ALP: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^210.7± 6.81
Tinostamustine 220 mg/m^214.7± 5.13
AST: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^23.0± 1.00
Tinostamustine 220 mg/m^22.0± 4.36
Lactate dehydrogenase: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-21.0± 11.31
Tinostamustine 220 mg/m^24.0± 2.83
Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Renal Function Parameters Secondary · Baseline (Day -1), Day 100

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.

Creatinine: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^214.1440± 18.71075
Tinostamustine 220 mg/m^225.6360± 8.43282
Bilirubin: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^2-1.710± 3.4200
Tinostamustine 220 mg/m^2-3.420± 6.1655
Direct Bilirubin: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^20.855± 1.2092
Tinostamustine 220 mg/m^2-3.420± NA
Indirect Bilirubin: Change at Day 100
GroupValue95% CI
Tinostamustine 180 mg/m^20.855± 1.2092
Tinostamustine 220 mg/m^2-6.840± NA
Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Total Protein Secondary · Baseline (Day -1), Day 100

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

GroupValue95% CI
Tinostamustine 180 mg/m^213.67± 11.372
Tinostamustine 220 mg/m^230.13± 32.309
Phase 1 and 2: Time to Reach Maximum Plasma Concentration (Tmax) of Tinostamustine and Its Metabolites Secondary · Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

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

EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^20.750.50 – 0.75
Tinostamustine 220 mg/m^20.750.50 – 0.75
M2-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^21.001.00 – 1.00
Tinostamustine 220 mg/m^21.000.75 – 3.00
M8-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^20.750.50 – 0.75
Tinostamustine 220 mg/m^21.000.50 – 1.00
Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Tinostamustine and Its Metabolites Secondary · Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

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

EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^22270± 910
Tinostamustine 220 mg/m^23070± 1320
M2-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^22.85± 1.45
Tinostamustine 220 mg/m^22.23± 0.633
M8-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^252.4± 4.58
Tinostamustine 220 mg/m^260.4± 11.5
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 Secondary · Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion

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.

EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^22858.44± 1475.82
Tinostamustine 220 mg/m^24922.66± 2056.86
M2-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^2NA± NA
Tinostamustine 220 mg/m^26.65± 3.75
M8-EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^260.42± 20.36
Tinostamustine 220 mg/m^2100.75± 20.01
Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of Tinostamustine and Its Metabolites Secondary · Pre-infusion, 0.50, 0.75, 1, 3, 6 hours post-infusion

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.

EDO-S101
GroupValue95% CI
Tinostamustine 180 mg/m^2NA± NA
Tinostamustine 220 mg/m^24887.16± 2052.21

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of tinostamustine up to end of study (up to 6 months). Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tinostamustine (180 mg/m^2)
Serious: 1/3 (33%)
Deaths: 0/3
Tinostamustine (220 mg/m^2)
Serious: 2/3 (67%)
Deaths: 0/3

Serious adverse events (4 terms)

ReactionSystemTinostamustine (180 mg/m^2)Tinostamustine (220 mg/m^2)
Electrocardiogram QT prolongedInvestigations
Febrile neutropeniaBlood and lymphatic system disorders
PneumoniaInfections and infestations
Atrial fibrillationCardiac disorders
Other adverse events (48 terms — click to expand)

ReactionSystemTinostamustine (180 mg/m^2)Tinostamustine (220 mg/m^2)
Electrocardiogram QT prolongedInvestigations
AnaemiaBlood and lymphatic system disorders
Febrile neutropeniaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
DyspepsiaGastrointestinal disorders
HypokalaemiaMetabolism and nutrition disorders
HypophosphataemiaMetabolism and nutrition disorders
HaematuriaRenal and urinary disorders
HypotensionVascular disorders
NeutropeniaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
ConstipationGastrointestinal disorders
Abdominal painGastrointestinal disorders
Anal incontinenceGastrointestinal disorders
StomatitisGastrointestinal disorders
FatigueGeneral disorders
PneumoniaInfections and infestations
Upper respiratory tract infectionInfections and infestations
FallInjury, poisoning and procedural complications
Patella fractureInjury, poisoning and procedural complications
Lymphocyte count decreasedInvestigations
Platelet count decreasedInvestigations
Blood creatinine increasedInvestigations
Blood lactate dehydrogenase increasedInvestigations
Neutrophil count decreasedInvestigations
HypocalcaemiaMetabolism and nutrition disorders
HypomagnesaemiaMetabolism and nutrition disorders
AcidosisMetabolism and nutrition disorders
Diabetes mellitusMetabolism and nutrition disorders
HyperglycaemiaMetabolism and nutrition disorders
HyperuricaemiaMetabolism and nutrition disorders
HypoalbuminaemiaMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Spinal painMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
ParaesthesiaNervous system disorders
Restless legs syndromeNervous system disorders
Thrombosis in deviceProduct Issues

Most-reported serious reactions: Electrocardiogram QT prolonged, Febrile neutropenia, Pneumonia, Atrial fibrillation.

Data from ClinicalTrials.gov NCT03687125 adverse events section.

Sponsor's own description

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.

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Epigenetics-targeted drugs: current paradigms and future challenges.
    Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
  2. Targeting histone deacetylases for cancer therapy: Trends and challenges.
    Liang T, Wang F, Elhassan RM, Cheng Y, et al · · 2023 · cited 128× · PMID 37425042 · DOI 10.1016/j.apsb.2023.02.007
  3. Processes and therapeutic perspectives of acylation modifications of lysine and cysteine in tumors.
    Jiang J, Chen J, Huang S, Tian Y, et al · · 2026 · PMID 41630001 · DOI 10.1186/s12964-026-02707-4

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