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
Treatment with TINOSTAMUSTINETreatment Arm

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 patients with relapsed/ refractory multiple
      myeloma (MM). (ASCT is defined as salvage if the patient 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 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 patients initially will be enrolled. If ≤25 patients of these initial 31
      patients experience a response, then no additional patients will be enrolled. However, if >25
      patients in Stage 1 of Phase 2 experience a response, then enrollment in this cohort will
      continue, with up to 71 patients enrolled. In Phase 2 of the study, all patients will receive
      tinostamustine at the RP2D administered in Phase 1 according to the same schedule. After
      provision of written informed consent, patients will be screened for study eligibility within
      28 days before Day 1 (the day of ASCT). Patients 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.

      Patients 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
Treatment ArmExperimentalConditioning Treatment with TINOSTAMUSTINE for salvage ASCT and Relapse/Refractory Multiple Myeloma
  • Treatment with TINOSTAMUSTINE

Eligibility Criteria

        Inclusion Criteria:

          1. Patient has MM and:

               1. Has received prior ASCT after standard first-line induction treatment.

               2. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18
                  months in Phase 2.

                  Progression Free Interval is defined as the time from date of ASCT to PD.

               3. Received treatment with ≤3 prior lines of therapy. A line of therapy is defined
                  as 1 or more cycles of a planned treatment program. When patients have undergone
                  sequential phases of treatment without intervening progression, such as
                  induction, collection of peripheral blood stem cells, 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 (Garderet et al, 2017).

          2. CR, VGPR, PR, or minimal response (MR) to latest of salvage chemotherapy at relapse,
             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 patients 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 patient with a large number of available PBSCs to permit
             subsequent ASCT, as patients 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 <3 at Screening.

          7. Creatinine clearance ≥40 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% 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) >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:

        Patients 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

        2. Myocardial infarction (MI) or stroke within 6 months before Screening. 3. Uncontrolled
        acute infection. 4. HCT-CI >6 points. 5. 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.

        6. Major coagulopathy or bleeding disorder. 7. 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.

        8. Lack of cooperation to allow study treatment as outlined in this protocol. 9. Pregnancy
        or lactating female patients. 10. 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.

        11. Receiving treatment with drugs known to prolong the QT/QTc interval. 12. QTc interval
        (Fridericia's formula) >450 msec, based on the mean of triplicate Screening 12-lead ECGs.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine objective response rate (ORR) based on the IMWG Response Criteria
Time Frame:Day 100 (±7 days) post-autologous stem cell transplant (ASCT)
Safety Issue:
Description:complete response [CR], very good partial response [VGPR] and partial response [PR] based on the IMWG Response Criteria for MM

Secondary Outcome Measures

Measure:Objective response rate (ORR) for patients treated at the recommended phase 2 dose
Time Frame:Day 100 (±7 days) post-autologous stem cell transplant (ASCT)
Safety Issue:
Description:ORR, and, in patients who achieve CR, minimal residual disease negativity (MRD-N), as determined by next generation flow cytometry according to the IMWG Criteria for MM
Measure:Incidence of neutrophil and platelet engraftment failure
Time Frame:Approximately 4 years
Safety Issue:
Description:
Measure:Duration of cytopenia (absolute neutrophil count [ANC] ≤0.5×109/L, platelet count ≤20×109/L)
Time Frame:Day 100 (±7 days) post-autologous stem cell transplant (ASCT)
Safety Issue:
Description:
Measure:Cumulative incidence of treatment related mortality (TRM)
Time Frame:Approximately 4 years
Safety Issue:
Description:
Measure:Transplant-related non-hematologic toxicity as defined by CTCAE 4.03 stratified by hematopoietic cell transplantation comorbidity index
Time Frame:Day 100 (±7 days) post-autologous stem cell transplant (ASCT)
Safety Issue:
Description:
Measure:Incidence of adverse events and serious adverse events according to CTCAE 4.03
Time Frame:Approximately 4 years
Safety Issue:
Description:
Measure:Incidence of change from baseline in routine safety hematology and clinical chemistry results
Time Frame:Approximately 4 years
Safety Issue:
Description:

Details

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

Last Updated