Clinical Trials /

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

NCT02576496

Description:

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

Related Conditions:
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-Cell Lymphoma
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Mycosis Fungoides
  • Peripheral T-Cell Lymphoma, Not Otherwise Specified
  • Sezary Syndrome
  • T-Cell Prolymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Tinostamustine, First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: EDO-S101-1001
  • NCT ID: NCT02576496

Conditions

  • Hematological Malignancies
  • Multiple Myeloma
  • Hodgkin's Lymphoma
  • Peripheral T-cell Lymphoma
  • Cutaneous T Cell Lymphoma
  • T-cell Prolymphocytic Leukemia

Interventions

DrugSynonymsArms
TinostamustineTinostamustine (EDO-S101)

Purpose

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

Detailed Description

      Tinostamustine is a new chemical entity, a first-in-class fusion molecule of an alkylator,
      bendamustine and a histone-deacetylase inhibitor (HDACi), vorinostat. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Tinostamustine (EDO-S101)ExperimentalEDO-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
  • Tinostamustine

Eligibility Criteria

        Inclusion Criteria:

          1. Execute an informed consent.

          2. Patients age ≥18 years at signing the informed consent.

          3. Diagnosis of relapsed or refractory lymphoid malignancy for which there are no
             available therapies.

          4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2

          5. Absolute Neutrophil Count >1,000 µL

          6. Platelets ≥75,000 µL

          7. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of
             normal (ULN).

          8. Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.

          9. Creatinine ≤1.5 x ULN.

         10. Serum potassium and magnesium within normal range at baseline (supplementation is
             permissible).

         11. Males and females of child-bearing potential, and their partners, must be willing to
             use at least two effective forms of birth control during the study drug administration
             and for at least 90 days after the administration of the study drug to be eligible to
             participate. Vasectomized partners and patients must be willing to use a secondary
             method of effective birth control. Sexual abstinence is considered a highly effective
             method only if defined as refraining from heterosexual intercourse during the entire
             period of risk associated with the study treatment. The reliability of sexual
             abstinence needs to be evaluated in relation to the duration of the clinical trial and
             the preferred and usual lifestyle of the patient.

        Specific Eligibility Criteria for Each Patient Cohort in Stage 2 Phase of the Study

        Cohort 1: relapsed/refractory multiple myeloma

        1. At least one line and a maximum of four prior standard systemic therapies and no other
        standard therapy available with proven clinical benefit.

        Cohort 2: relapsed/refractory Hodgkin's lymphoma

        1. At least three lines of prior therapy and no other standard therapy available with
        proven clinical benefit.

        Cohort 3: relapsed/refractory peripheral T-cell lymphoma (PTCL)

          1. Only PTCL patients with histologically or cytologically confirmed PTCL-not otherwise
             specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) or anaplastic
             large-cell lymphoma (ALCL).

          2. At least one line of prior combination therapy and no other standard therapy available
             with proven clinical benefit.

        Cohort 4: relapsed/refractory cutaneous T-cell lymphoma (CTCL), subtypes mycosis fungoides
        (MF) and Sézary syndrome (SS)

          1. Only CTCL patients with histologically or cytologically confirmed MF or SS with stage
             IIb to IVb disease based on modified ISCL/EORTC staging.

          2. At least one line and a maximum of four prior standard systemic therapies and no other
             standard therapy available with proven clinical benefit.

        Cohort 5: relapsed/refractory T-cell Prolymphocytic leukemia (T-PLL)

        1. A maximum of two lines of prior therapy and no other standard therapy available with
        proven clinical benefit. Patients ineligible for treatment with alemtuzumab can be
        included.

        Exclusion Criteria:

          1. Patients with any central nervous system involvement.

          2. Diagnosis of acute leukemia or any patient that has been treated with fludarabine.

          3. Any patient who has relapsed within 100 days of stem cell infusion following an
             allogenic or an autologous bone marrow transplant.

          4. Patients with corrected QT (QTc) interval (Fridericia's formula) > 450 msec.

          5. Patients who are on treatment with drugs known to prolong the QT/QTc interval.

          6. Any serious medical condition that interferes with adherence to study procedures.

          7. Patients with a history of another malignancy diagnosed within three years of study
             enrollment excluding basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          8. Pregnant or breast feeding females.

          9. New York Heart Association (NYHA) stage III/IV congestive heart failure. The following
             arrhythmias not adequately controlled, active: atrial fibrillation/flutter with poor
             rate control, documented sustained ventricular tachycardia (defined as >30 seconds or
             requiring cardioversion before 30 seconds have elapsed) or TdP.

         10. Active infections, or other significant co-morbidities [(e.g., active central nervous
             system metastases and/or carcinomatous meningitis, active infection requiring systemic
             therapy, history of human immunodeficiency virus (HIV) infection, or active Hepatitis
             B or Hepatitis C.

         11. Previous cancer therapies within four (4) weeks or 5 half-lives, whichever is shorter,
             of dosing unless the patient has recovered to eligibility levels prior to treatment in
             this study.

         12. Use of other investigational agents within 30 days or 5 half-lives prior to the first
             dose of study drug unless patient has recovered from any related toxicities ≥ Grade 1.

         13. Steroid treatment within seven (7) days prior to study treatment. Patients that
             require intermittent use of bronchodilators, topical steroids or local steroid
             injections will not be excluded from the study. Patients who have been stabilized to
             10 mg PO QD or less seven (7) days prior to study drug administration are allowed.

         14. Patients on Valproic Acid for any indication (epilepsy, mood disorder) must be
             excluded from the trial or must stop using the medication and have a wash out period
             of 3.5 days prior to first dose of tinostamustine (C1D1).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:10-20 months from beginning of stage 2
Safety Issue:
Description:Determine overall response rate

Secondary Outcome Measures

Measure:Time to objective response
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Evaluate time to objective response by cohort
Measure:Duration of response
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Evaluate duration of response
Measure:Progression free survival (PFS)
Time Frame:32-36 months after beginning stage 2
Safety Issue:
Description:Determine time to progression free survival time for patients who received the RP2D
Measure:Overall Survival (OS)
Time Frame:32-36 months after beginning stage 2
Safety Issue:
Description:Determine the overall survival time for patients who received the RP2D
Measure:Maximum Plasma Concentration (Cmax)
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Determine Cmax using the PK population
Measure:Time to Reach Maximum Concentration (Tmax)
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Determine Tmax using the PK population
Measure:Time taken for the plasma concentration to fall by half its original value (t1/2)
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Determine t1/2 using the PK population
Measure:Area Under Curve (AUC)
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:Determine area under the plasma drug concentration-time curve using the PK population
Measure:QT (QTc) analysis
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description:To perform a concentration corrected QT analysis
Measure:Number of patients with treatment-emergent adverse events (TEAEs). TEAEs will be assessed by NCI-CTCAE 4.03
Time Frame:10-20 months after beginning stage 2
Safety Issue:
Description: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)

Details

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

Trial Keywords

  • phase 1 clinical trial
  • multiple myeloma
  • Hodgkin's lymphoma
  • peripheral T-cell lymphoma
  • cutaneous T-cell lymphoma
  • T-cell Prolymphocytic Leukemia
  • tinostamustine

Last Updated

February 25, 2020