Tinostamustine Conditioning and Autologous Stem Cell

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma Progression, Multiple Myeloma With Failed Remission

Intervention / Treatment
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* Drug: Tinostamustine
* Procedure: Autologous Stem Cell Transplant (ASCT)


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 Does escalation followed by Phase 2 Expansion at MTD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tinostamustine 180 mg/m^2<br>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<br>* Participants received tinostamustine IV injection.<br>Procedure: Autologous Stem Cell Transplant (ASCT)<br>* Undergo autologous stem cell transplant<br>|
| Experimental: Tinostamustine 220 mg/m^2<br>Participants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1. | Drug: Tinostamustine<br>* Participants received tinostamustine IV injection.<br>Procedure: Autologous Stem Cell Transplant (ASCT)<br>* Undergo autologous stem cell transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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 | 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. | up to 6 months | 
| 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. | Up to 6 months | 
| Phase 1 and 2: Number of Participants With Treatment Related Mortality (TRM) | Number of participants with treatment related mortality was reported. | Up to 6 months | 
| 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). | Up to 6 months | 
| 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. | From first dose of tinostamustine up to end of study (up to 6 months) | 
| 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. | Baseline (Day -1), Day 30 | 
| 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. | Baseline (Day -1), Day 100 | 
| 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. | Baseline (Day -1), Day 100 | 
| 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. | Baseline (Day -1), Day 100 | 
| 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. | Baseline (Day -1), Day 100 | 
| 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. | Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion | 
| 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. | Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion | 
| 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. | Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion | 
| 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. | Pre-infusion, 0.50, 0.75, 1, 3, 6 hours post-infusion |