Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Tinostamustine

Tomas Janik, MD

The study is designed as an open label, multi-center, Phase 1 study of single agent tinostamustine, used as adjuvant treatment in patients with newly diagnosed GBM who are MGMT unmethylated and have completed concomitant treatment with temozolomide and radiation. Treatment with adjuvant tinostamustine will start within 5 weeks of completion of concomitant temozolomide and radiation. The study is designed to define the MTD by evaluating toxicities during dose escalation. Tinostamustine will be administered on Day 1 of a 21-day treatment cycle.

The total number of treatment cycles is 12 for patients who continue to benefit from treatment without disease progression or intolerable toxicity. Patients will enter a "3+3" design with dose escalation/de-escalation depending on safety from the last treated cohort.

Study of Tinostamustine for Adjuvant Treatment of Glioblastoma

A Phase 1 Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Tinostamustine, a Novel Alkylating and Deacetylase Inhibiting Molecule, as Adjuvant Treatment in Patients With Newly Diagnosed Unmethylated MGMT-promoter Glioblastoma

Toxicity will be evaluated according to the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) toxicity criteria

Response assessment in neuro-oncology (RANO) criteria (to assess mPFS, PFS, ORR, OS, duration of response \[DoR\])

Mundipharma Research Limited

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Symptoms and General Pathology

Multiple Myeloma

Neoplasms, Plasma Cell

Disease Progression

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

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.

Participants received single dose of tinostamustine 220 mg/m\^2 IV injection on Day -1 followed by ASCT on Day 1.

Participants received tinostamustine IV injection.

Autologous Stem Cell Transplant (ASCT)

Parameswaran Hari, MD

Dagmar Hess

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.

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.

Phase 1 Does escalation followed by Phase 2 Expansion at MTD

Tinostamustine Conditioning and Autologous Stem Cell

Phase 1/2 Open-label Trial of Tinostamustine Conditioning and Autologous Stem Cell Transplantation for Salvage Treatment in Relapsed / Refractory Multiple Myeloma (TITANIUM 1)

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.

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.

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

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.

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

Number of participants with treatment related mortality was reported.

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).

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.

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.

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.

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.

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.

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

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

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

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.

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.

Mundipharma-EDO GmbH

Safety population included all participants who received tinostamustine.

Participants received single dose of 180 mg/m\^2 tinostamustine IV injection on Day -1 followed by ASCT on Day 1.

Tinostamustine (180 mg/m^2)

Participants received single dose of 220 mg/m\^2 tinostamustine IV injection on Day -1 followed by ASCT on Day 1.

Tinostamustine (220 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.

Tinostamustine 180 mg/m^2

Participants received single dose of tinostamustine 220 mg/m\^2 IV injection followed by ASCT on Day 1.

Tinostamustine 220 mg/m^2

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race

Race/Ethnicity, Customized

Study was early terminated during Phase 1 due to sponsor decision on 17 April 2019 (adverse events limited administration of higher doses required to achieve myeloablative conditioning necessary in this population). Hence, no participants were enrolled in Phase 2 and efficacy analysis were not performed in the both Phase 1 and 2.

Terry Nichols

Participants received single dose of tinostamustine 180 mg/m\^2 IV injection on Day -1 followed by ASCT on Day 1.

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.

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

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.

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

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

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.

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

Phase 1 and 2: Duration of Cytopenia

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

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

Participants with TEAEs

Participants with TESAEs

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

Phase 1 and 2: Change From Baseline in Hematology Parameters

Bicarbonate: Change at Day 100

Calcium: Change at Day 100

Chloride: Change at Day 100

Glucose: Change at Day 100

Magnesium: Change at Day 100

Phosphate: Change at Day 100

Potassium: Change at Day 100

Sodium: Change at Day 100

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

ALT: Change at Day 100

ALP: Change at Day 100

AST: Change at Day 100

Lactate dehydrogenase: Change at Day 100

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.

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

Creatinine: Change at Day 100

Bilirubin: Change at Day 100

Direct Bilirubin: Change at Day 100

Indirect Bilirubin: Change at Day 100

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

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

EDO-S101

M2-EDO-S101

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.

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

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.

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

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. Here, number analyzed refers to the number of participants with available data for each specified category.

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

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

Overall Study

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

First-in-human administration of the combination of Tinostamustine and Nivolumab.

Elke Hiendlmeyer, Dr.

Christina Jodlauk

Roger von Moos, Prof.

Markus Joerger, Prof.

This trial is a first-in-human drug combination with the first-in-class alkylating histone deacetylase inhibition (HDACi) fusion molecule Tinostamustine (EDO-S101) and the anti-PD-1 monoclonal antibody Nivolumab in patients with refractory, locally advanced or metastatic melanoma.

Despite improvement of systemic treatment in patients with advanced melanoma, there is still unmet medical need in this group of patients. Tinostamustine is a medication without marketing authorization, while Nivolumab is approved for several tumor entities. The primary objective of this trial is to assesses the safety, tolerability and recommended dose of Tinostamustine in combination with Nivolumab in patients with advanced melanoma.Secondary objectives of this trial in patients with advanced solid tumors are to assess the preliminary efficacy of Tinostamustine when given in combination with Nivolumab and to characterize potential predictive biomarkers of the combination treatment of Tinostamustine and Nivolumab. The trial includeds patients with either histologically or cytologically confirmed inoperable stage III or metastatic stage IV melanoma with an indication for the regular systemic treatment with Nivolumab and a maximum of 1 prior systemic palliative line of treatment.

this is an open label, non-randomized, Phase IB clinical trial studying a new anticancer drug combination

Tinostamustine and Nivolumab in Advanced Melanoma

Open Label, Non-randomized, Phase IB Study to Characterize Safety, Tolerability and Recommended Dose of Tinostamustine and Nivolumab in Patients With Refractory, Locally Advanced or Metastatic MelAnoma

Dose limiting toxicity defined as any of the following AEs (according to CTCAE v 4.03) occurring during the first 42 days of study treatment for each study patient of the safety part of the trial, and regarded to be related (possibly, probably or definitely) to Tinostamustine:

* CTC °4 neutropenia during ≥ 5 days
* Febrile neutropenia
* CTC °4 thrombocytopenia or CTC° 3 thrombocytopenia with bleeding
* Any other ≥ CTC °4 hematological AE
* ≥ CTC °3 AST or ALT elevations for \>7 days, or CTC °4 AST/ALT elevations for any duration
* ≥ CTC °3 nausea, vomiting or diarrhea despite appropriate pre-medication
* Any other ≥ CTC °3 non-hematological study-treatment-related AE, excluding alopecia
* ≥ CTC °3 uveitis, pneumonitis, bronchospasm, neurological toxicity, hypersensi-tivity reactions or infusion reactions that result in discontinuation of study treat-ment
* Any study treatment-related AE that results in a delay of the administration of Tinostamustine of at least 4 weeks

All adverse events (AE) including laboratory safety parameters according to CTCAE v.4.03

Objective tumor response according to RECIST 1.1 and iRECIST

Progression-free survival (PFS, iPFS), defined as the time between registration to the study and the time of disease progression according to RECIST v.1.1 and iRECIST or death of the patient, whatever occurs first

Overall survival (OS) from registration of study participation

Markus Joerger

Chair Clinical Research Unit

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Hematologic Neoplasms

Hodgkin Disease

Lymphoma, T-Cell, Cutaneous

Lymphatic Diseases

Lymphoma, Non-Hodgkin

Lymphosarcoma

Peripheral T-cell Lymphoma

Hodgkin Lymphoma

Cutaneous T-cell Lymphoma

EDO-S101, IV, 20mg/m2 up to 150mg/m2 Day1 of each 21 day cycle-Stage 1; EDO-S101,IV, 40mg/m2 up to 60mg/m2 on Day 1 and Day 15 of 28 day cycle in multiple myeloma patients and IV, 40mg/m2 up to 100mg/m2 on Day 1 of 21 day cycle in lymphoma patients-Stage 2

Pier L Zinzani, MD,PhD

This study evaluates the efficacy, safety and pharmacokinetics of tinostamustine (EDO-S101) in patients with relapsed/refractory hematologic malignancies. All patients will receive tinostamustine.

Tinostamustine is a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule. It is anticipated that tinostamustine may have activity in various hematological malignancies and solid tumors.

The study consists of 2 stages:

* Stage 1: Dose Escalation to determine Maximum Tolerated Dose (MTD) at the optimal infusion time and the pharmacokinetic (PK) profiles; is expected to enroll between 21 and 48 patients. Stage 1 has now been completed.
* Stage 2: Expansion in five Cohorts, in which approximately 12-16 patients will be enrolled per cohort, for a maximum of 70 patients.

In Stage 1, tinostamustine doses were escalated following the standard 3+3 design. The decision to escalate to the next dose level occurred after all cohort patients completed 3 weeks (21 days) of observation and have been evaluated for safety and toxicity.The starting dose was a 1 hour infusion of 20 mg/m2, and the maximum dose level was 150 mg/m2. Reduced infusion times of 45 minutes and 30 minutes were assessed once the maximum tolerated dose at a 1-hour infusion was determined.

In Stage 2, five cohorts of patients (with relapsed/refractory multiple myeloma (MM); relapsed/refractory Hodgkin's lymphoma; relapsed/refractory peripheral T-cell lymphoma (PTCL); relapsed/refractory cutaneous T-cell lymphoma (CTCL); and relapsed/refractory T-cell Prolymphocytic leukemia (T-PLL) will be enrolled and treated at the recommended Phase 2 dose (RP2D) based on results of Stage 1. For MM patients, treatment will occur on Day 1 and Day 15 of a 28 day cycle. For lymphoma patients, treatment will occur on Day 1 of a 21 day cycle. Patients in each stage of the study are expected to receive a median of four Cycles of therapy, and the maximum number of treatment Cycles allowed is 12.

A sub study portion was added to the protocol as an amendment. In the sub study 6 patients will be treated with 100mg/m2 tinostamustine infusion delivered over 100 minutes.

Study of Tinostamustine, First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies

A Phase 1 Trial to Investigate the Safety, Pharmacokinetic Profiles and the Efficacy of Tinostamustine, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies

relevant patient listing data of de-identified patients may be reviewed

To characterize the effect of tinostamustine at a dose of 100 mg/m2 on cardiac repolarization (QTcF) and other ECG parameters

Determine clinical benefit rate by cohort

Number of participants with treatment-related adverse events as assessed by CTCAE V4.03

Evaluate time to objective response by cohort

Determine time to progression free survival time for patients who received the RP2D

Determine the overall survival time for patients who received the RP2D

Determine area under the plasma drug concentration-time curve using the PK population

To perform a concentration corrected QT analysis

Patient safety data will be summarized by disease cohort as well as overall disease cohorts pooled (i.e., MM, Hodgkin's lymphoma, non-Hodgkin's lymphoma, PTCL, T- PLL)

Gliosarcoma

Anti-Infective Agents

Benzimidazole

Anthelmintics

Antiparasitic Agents

Patients who have completed TMZ and RT receive tinostamustine IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Patients who have received no treatment other than surgery undergo RT 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive tinostamustine over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Radiation Therapy

Shiao-Pei S Weathers

This phase I trial studies the side effects and best dose of tinostamustine (EDO-S101) given with or without radiation therapy in treating patients with newly diagnosed MGMT-unmethylated glioblastoma. Tinostamustine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth in patients with glioblastoma.

PRIMARY OBJECTIVES:

I. To characterize the safety profile and determine the maximum tolerated dose (MTD) of tinostamustine (EDO-S101) in the adjuvant phase of therapy for patients with newly diagnosed MGMT-promoter unmethylated glioblastoma (GB) post chemoradiation with temozolomide. (Stage 1) II. To characterize the safety profile and determine the MTD of EDO-S101 when given as a single agent in the concomitant phase with radiation therapy (RT) in patients with newly diagnosed GB who are MGMT-promoter unmethylated. (Stage 2) III. To confirm the MTD of EDO-S101 in the concomitant phase and adjuvant phase in an expanded population of newly diagnosed GB patients who are MGMT-promoter un-methylated. (Dose Expansion Group)

SECONDARY OBJECTIVE:

I. To assess anti-tumor activity for patients with newly diagnosed GB who are MGMT-promoter unmethylated based on progression-free survival (PFS), overall survival (OS), and overall response rate (ORR).

EXPLORATORY OBJECTIVE:

I. Profiling tumor deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microRNA and epigenetic profiling (DNA methylation) and evaluation of whole exome sequencing, RNA sequencing, microRNA sequencing and cell-free circulating tumor DNA (ctDNA) and correlate with outcome.

OUTLINE: This is a dose-escalation study of tinostamustine. Patients are assigned to 1 of 2 stages.

STAGE 1: Patients who have completed temozolomide (TMZ) and radiation therapy (RT) receive tinostamustine intravenously (IV) over 60 minutes on day 1. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

STAGE 2: Patients who have received no treatment other than surgery undergo RT 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive tinostamustine over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Tinostamustine for Adjuvant Treatment of Glioblastoma	NCT05432375	Glioblastoma Mu...	Tinostamustine	18 Years -	Mundipharma Research Limited
Tinostamustine Conditioning and Autologous Stem Cell	NCT03687125	Multiple Myelom... Multiple Myelom... Multiple Myelom...	Tinostamustine Autologous Stem...	18 Years - 75 Years	Mundipharma-EDO GmbH
Tinostamustine and Nivolumab in Advanced Melanoma	NCT03903458	Malignant Melan...	Tinostamustine	18 Years -	Cantonal Hospital of St. Gallen
Study of Tinostamustine, First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies	NCT02576496	Hematological M... Multiple Myelom... Hodgkin's Lymph... Cutaneous T Cel...	Tinostamustine	18 Years -	Mundipharma Research Limited
Study of Tinostamustine, First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies	NCT02576496	Hematological M... Multiple Myelom... Hodgkin's Lymph... Cutaneous T Cel...	Tinostamustine	18 Years -	Mundipharma Research Limited
Study of Tinostamustine for Adjuvant Treatment of Glioblastoma	NCT05432375	Glioblastoma Mu...	Tinostamustine	18 Years -	Mundipharma Research Limited
Tinostamustine With or Without Radiation Therapy in Treating Patients With Newly Diagnosed MGMT-Unmethylated Glioblastoma	NCT03452930	Glioblastoma Gliosarcoma MGMT-Unmethylat...	Radiation Thera... Tinostamustine	18 Years -	M.D. Anderson Cancer Center
Tinostamustine Conditioning and Autologous Stem Cell	NCT03687125	Multiple Myelom... Multiple Myelom... Multiple Myelom...	Tinostamustine Autologous Stem...	18 Years - 75 Years	Mundipharma-EDO GmbH
Tinostamustine and Nivolumab in Advanced Melanoma	NCT03903458	Malignant Melan...	Tinostamustine	18 Years -	Cantonal Hospital of St. Gallen

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