Clinical Trials /

Tinostamustine Conditioning and Autologous Stem Cell

NCT03687125

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: EDO-S101-1004
  • SECONDARY ID: 2018-001907-35
  • NCT ID: NCT03687125

Conditions

  • Multiple Myeloma in Relapse
  • Multiple Myeloma Progression
  • Multiple Myeloma With Failed Remission

Interventions

DrugSynonymsArms
TinostamustineTinostamustine 180 mg/m^2

Purpose

Phase 1 The primary objectives of Phase 1 of this study are to: - Establish the safety, toxicity, and maximum tolerated dose (MTD) of the tinostamustine conditioning regimen. - Identify the recommended Phase 2 dose (RP2D) of tinostamustine for use in the Phase 2 portion of the study. The secondary objective of Phase 1 of this study is to: - Investigate the pharmacokinetics (PK) of tinostamustine.

Detailed Description

      Study Design (Methodology):

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

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

Trial Arms

NameTypeDescriptionInterventions
Tinostamustine 180 mg/m^2ExperimentalParticipants 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.
  • Tinostamustine
Tinostamustine 220 mg/m^2ExperimentalParticipants received single dose of tinostamustine 220 mg/m^2 IV injection on Day -1 followed by ASCT on Day 1.
  • Tinostamustine

Eligibility Criteria

        Inclusion Criteria:

          1. 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.

          2. 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.

          3. 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.)

          4. Has available autologous peripheral blood stem cell (PBSC) product with CD34 cell dose
             >= 2×106 cells/kg. The product could be from a collection prior to first ASCT or later
             second collection. (Note that, although not required, in Phase 1, the Investigator
             should consider enrolling 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.)

          5. Age 18-75 years.

          6. Eastern Cooperative Oncology Group (ECOG) performance status score lesser than (<) 3
             at Screening.

          7. Creatinine clearance >= 40 milliliter per minute (mL/min), as determined by a local
             laboratory using the Cockcroft-Gault equation within 28 days before ASCT.

          8. Left ventricular ejection fraction (LVEF) >= 40 percent (%) within 28 days before
             ASCT.

          9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1),
             forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) greater
             than (>) 50% predicted within 28 days before ASCT.

         10. Adequate liver function, as defined by an alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) <= 2.5 × the upper limit of normal (ULN) and bilirubin <= 1.5 ×
             ULN within 28 days before ASCT.

         11. Potassium within the local laboratory's normal range. (Potassium supplementation is
             permissible.)

        Exclusion Criteria:

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

          1. History of central nervous system (CNS) disease involvement.

          2. Primary or secondary plasma cell leukemia at any time point prior to transplant.

          3. Myocardial infarction (MI) or stroke within 6 months before Screening.

          4. Uncontrolled acute infection.

          5. Hematopoietic cell transplantation-comorbidity index (HCT-CI) > 6 points.

          6. 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.

          7. Major coagulopathy or bleeding disorder.

          8. 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.

          9. Lack of cooperation to allow study treatment as outlined in this protocol.

         10. Pregnancy or lactating female participants.

         11. 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.

         12. Receiving treatment with drugs known to prolong the QT/QTc interval.

         13. QTc interval (Fridericia's formula) > 450 millisecond (msec), based on the mean of
             triplicate Screening 12-lead electrocardiograms (ECGs).
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 2: Objective Response Rate (ORR) Based on International Myeloma Working Group (IMWG) Response Criteria
Time Frame:at Day 100 post-autologous stem cell transplant (ASCT)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Phase 1 and 2: Objective Response Rate (ORR) for Participants Treated at the Recommended Phase 2 Dose (RP2D)
Time Frame:at Day 100 post ASCT
Safety Issue:
Description:ORR for participants who achieved CR, minimal residual disease negativity (MRD-N), was determined by next generation flow cytometry according to the IMWG Criteria.
Measure:Phase 1 and 2: Number of Participants With Neutrophil and Platelet Engraftment Failure
Time Frame:up to 6 months
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Duration of Cytopenia
Time Frame:Up to 6 months
Safety Issue:
Description:Duration of cytopenia i.e ANC <= 0.5×10^9/L, and platelet count <= 20×10^9/L.
Measure:Phase 1 and 2: Number of Participants With Treatment Related Mortality (TRM)
Time Frame:Up to 6 months
Safety Issue:
Description:Number of participants with treatment related mortality was reported.
Measure:Phase 1 and 2: Number of Participants With Transplant-related Non-hematologic Grade 3 Toxicity
Time Frame:Up to 6 months
Safety Issue:
Description: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).
Measure:Phase 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time Frame:From first dose of tinostamustine up to end of study (up to 6 months)
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Change From Baseline in Hematology Parameters
Time Frame:Baseline (Day -1), Day 30
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Electrolytes
Time Frame:Baseline (Day -1), Day 100
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Liver Function Parameters
Time Frame:Baseline (Day -1), Day 100
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Renal Function Parameters
Time Frame:Baseline (Day -1), Day 100
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Change From Baseline in Clinical Serum Chemistry Tests: Total Protein
Time Frame:Baseline (Day -1), Day 100
Safety Issue:
Description:Clinical serum chemistry tests included total protein. Change from baseline in clinical serum chemistry tests i.e. total protein at Day 100 were reported.
Measure:Phase 1 and 2: Time to Reach Maximum Plasma Concentration (Tmax) of Tinostamustine and Its Metabolites
Time Frame:Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
Safety Issue:
Description:Tmax was defined as time to reach maximum plasma concentration. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.
Measure:Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Tinostamustine and Its Metabolites
Time Frame:Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
Safety Issue:
Description:Cmax was defined as maximum observed plasma concentration. Tinostamustine (EDO-S101) and its metabolites included M2-EDO-S101 and M8-EDO-S101.
Measure: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
Time Frame:Pre-infusion, 0.50, 0.75, 1, 3, 6, 24, 48 hours post-infusion
Safety Issue:
Description: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.
Measure:Phase 1 and 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of Tinostamustine and Its Metabolites
Time Frame:Pre-infusion, 0.50, 0.75, 1, 3, 6 hours post-infusion
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Mundipharma-EDO GmbH

Last Updated

June 18, 2021