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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02576496
Recruitment Status : Recruiting
First Posted : October 15, 2015
Last Update Posted : June 2, 2021
Information provided by (Responsible Party):
Mundipharma-EDO GmbH

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

Condition or disease Intervention/treatment Phase
Hematological Malignancies Multiple Myeloma Hodgkin's Lymphoma Cutaneous T Cell Lymphoma Drug: Tinostamustine Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 111 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : March 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Arm Intervention/treatment
Experimental: Tinostamustine (EDO-S101)
EDO-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
Drug: Tinostamustine

Primary Outcome Measures :
  1. Overall response rate [ Time Frame: 10-20 months from beginning of stage 2 ]
    Determine overall response rate

  2. Clinical benefit rate by cohort [ Time Frame: 10-20 months from beginning of stage 2 ]
    Determine clinical benefit rate by cohort

  3. Safety of selected doses in expanded population [ Time Frame: 36 months from beginning stage 2 ]
    Number of participants with treatment-related adverse events as assessed by CTCAE V4.03

Secondary Outcome Measures :
  1. Time to objective response [ Time Frame: 10-20 months after beginning stage 2 ]
    Evaluate time to objective response by cohort

  2. Duration of response [ Time Frame: 10-20 months after beginning stage 2 ]
    Evaluate duration of response

  3. Progression free survival (PFS) [ Time Frame: 32-36 months after beginning stage 2 ]
    Determine time to progression free survival time for patients who received the RP2D

  4. Overall Survival (OS) [ Time Frame: 32-36 months after beginning stage 2 ]
    Determine the overall survival time for patients who received the RP2D

  5. Maximum Plasma Concentration (Cmax) [ Time Frame: 10-20 months after beginning stage 2 ]
    Determine Cmax using the PK population

  6. Time to Reach Maximum Concentration (Tmax) [ Time Frame: 10-20 months after beginning stage 2 ]
    Determine Tmax using the PK population

  7. Time taken for the plasma concentration to fall by half its original value (t1/2) [ Time Frame: 10-20 months after beginning stage 2 ]
    Determine t1/2 using the PK population

  8. Area Under Curve (AUC) [ Time Frame: 10-20 months after beginning stage 2 ]
    Determine area under the plasma drug concentration-time curve using the PK population

  9. QT (QTc) analysis [ Time Frame: 10-20 months after beginning stage 2 ]
    To perform a concentration corrected QT analysis

  10. 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 ]
    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)

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Patient willing and able to sign an informed consent.
  2. Patients age ≥18 years at signing the informed consent.
  3. Life expectancy > 3 months.
  4. Diagnosis of relapsed or refractory lymphoid malignancy for which there are no available therapies.
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  6. Absolute Neutrophil Count >1,000 µL
  7. Platelets ≥100,000 µL
  8. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of normal (ULN).
  9. Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.
  10. Creatinine ≤1.5 x ULN.
  11. Serum potassium and magnesium at least at the lowest limit of normal (LLN) at baseline(before every IMP administration; if it is below LNN, (supplementation is permissible).
  12. 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 five 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 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.

Exclusion Criteria:

  1. Patients with any central nervous system involvement.
  2. Patient who had a hematologic malignancy that has transformed.
  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 three (3) weeks of dosing as long as 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 .

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): NCT02576496

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Sponsors and Collaborators
Mundipharma-EDO GmbH
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Principal Investigator: Pier L Zinzani, MD,PhD University of Bologna Medical Center, Bologna
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Responsible Party: Mundipharma-EDO GmbH Identifier: NCT02576496    
Other Study ID Numbers: EDO-S101-1001
First Posted: October 15, 2015    Key Record Dates
Last Update Posted: June 2, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: relevant patient listing data of de-identified patients may be reviewed
Keywords provided by Mundipharma-EDO GmbH:
phase 1 clinical trial
multiple myeloma
Hodgkin's lymphoma
cutaneous T-cell lymphoma
Additional relevant MeSH terms:
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Multiple Myeloma
Hodgkin Disease
Lymphoma, T-Cell
Hematologic Neoplasms
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoma, Non-Hodgkin
Neoplasms by Site