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Tinostamustine Conditioning and Autologous Stem Cell (TITANIUM1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03687125
Recruitment Status : Terminated (Sponsor decisionbased on adverse events limiting administration of higher doses required to achieve myeoblative conditioning necessary in this population)
First Posted : September 27, 2018
Last Update Posted : June 13, 2019
Information provided by (Responsible Party):
Mundipharma-EDO GmbH

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma in Relapse Multiple Myeloma Progression Multiple Myeloma With Failed Remission Drug: Treatment with TINOSTAMUSTINE Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Phase 1 Does escalation followed by Phase 2 Expansion at MTD
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 19, 2018
Actual Primary Completion Date : March 15, 2019
Actual Study Completion Date : March 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Treatment Arm
Conditioning Treatment with TINOSTAMUSTINE for salvage ASCT and Relapse/Refractory Multiple Myeloma
Drug: Treatment with TINOSTAMUSTINE
Conditioning treatment with TINOSTAMUSTINE

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

  2. During the Phase 1 portion, determine dose limiting toxicities (DLT) according to CTCAE 4.03 [ Time Frame: within 30 days post ASCT ]
    defined as at least possibly related to tinostamustine: (1) delayed engraftment (>30 days after ASCT) where subject has not met criteria for both neutrophil (first of 3 consecutive days with ANC >0.5×109/L) and platelet engraftment (first of 3 consecutive days of plt count >20×109/L without plt transfusion in the prior 7 days) (2) QTcF >500 msec or >60 msec increase from baseline with duration of >30 minutes or ≥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 hrs), infection, dyspnea, hypoxia, pneumonitis, pain, dysphagia, oral mucositis, anorexia, flu-like or engraftment syndrome, weight loss, insomnia, decreased calcium, sodium, magnesium, potassium, and/or phosphate, increased AST, ALT, bilirubin, and/or alkaline phosphatase, and alopecia

Secondary Outcome Measures :
  1. 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) ]
    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

  2. Incidence of neutrophil and platelet engraftment failure [ Time Frame: Approximately 4 years ]
  3. 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) ]
  4. Cumulative incidence of treatment related mortality (TRM) [ Time Frame: Approximately 4 years ]
  5. 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) ]
  6. Incidence of adverse events and serious adverse events according to CTCAE 4.03 [ Time Frame: Approximately 4 years ]
  7. Incidence of change from baseline in routine safety hematology and clinical chemistry results [ Time Frame: Approximately 4 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03687125

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United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, Kansas
University of Kansas Medical Center Kansas City
Kansas City, Kansas, United States, 66160
United States, New York
Memorial Sloan Kettering Cancer Centre
New York, New York, United States, 10065
United States, North Carolina
Carolinas Healthcare System
Charlotte, North Carolina, United States, 28204
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37203
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Wisconsin
Froedtert & Medical College of Wisconsin, Cancer Center - Froedtert Hospital
Milwaukee, Wisconsin, United States, 53226
Oslo Myeloma Center, Oslo University Hospital
Oslo, Norway
Universitatsspital Basel
Basel, Switzerland
Universitatsspital Bern
Bern, Switzerland
Department of Clinical Research Oncology/Hematology, Kantonsspital St. Gallen
Saint Gallen, Switzerland
University Hospital Zurich
Zürich, Switzerland
Sponsors and Collaborators
Mundipharma-EDO GmbH
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Study Chair: Parameswaran Hari, MD Study Chair
Study Chair: Dagmar Hess 2nd Study Chair

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Responsible Party: Mundipharma-EDO GmbH Identifier: NCT03687125     History of Changes
Other Study ID Numbers: EDO-S101-1004
2018-001907-35 ( EudraCT Number )
First Posted: September 27, 2018    Key Record Dates
Last Update Posted: June 13, 2019
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases