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

  • days left to enroll
  • participants needed
  • sponsor
    Mundipharma Research Limited
Updated on 5 May 2022
hematologic malignancy
multiple myeloma
hodgkin's disease
systemic therapy
fungal infection
gilbert's syndrome
neutrophil count
prolymphocytic leukemia
follicular lymphoma
mantle cell lymphoma
t-cell lymphoma
peripheral t-cell lymphoma
angioimmunoblastic t-cell lymphoma
mycosis fungoides
sezary syndrome
refractory lymphoma
anaplastic large cell lymphoma
large cell lymphoma
marginal zone lymphoma
refractory multiple myeloma
refractory hodgkin lymphoma
cutaneous t-cell lymphoma
refractory peripheral t-cell lymphoma
t-cell prolymphocytic leukemia


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


Tinostamustine is a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule. 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.

A sub study portion was added to the protocol as an amendment. In the sub study 6 patients will be treated with 100mg/m2 tinostamustine infusion delivered over 100 minutes.

Condition Hematological Malignancies, Multiple Myeloma, Hodgkin's Lymphoma, Cutaneous T Cell Lymphoma
Treatment EDO-S101, Tinostamustine
Clinical Study IdentifierNCT02576496
SponsorMundipharma Research Limited
Last Modified on5 May 2022


Yes No Not Sure

Inclusion Criteria

Patient willing and able to sign an informed consent
Patients age ≥18 years at signing the informed consent
Diagnosis of relapsed or refractory lymphoid malignancy for which there are no available therapies
Life expectancy > 3 months
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Absolute Neutrophil Count >1,000 µL
Platelets ≥100,000 µL
Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome
Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of normal (ULN)
Creatinine ≤1.5 x ULN
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
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)
Specific Eligibility Criteria for Each Patient Cohort in Stage 2 Phase of the
Cohort 1: relapsed/refractory multiple myeloma (Recruitment to this cohort stopped Dec
Cohort 2: relapsed/refractory Hodgkin's lymphoma
) 1. At least one line of prior systemic therapy and no other standard therapy
clinical benefit
available with proven clinical benefit
At least two lines of prior therapy and no other standard therapy available with proven
Cohort 4: relapsed/refractory cutaneous T-cell lymphoma (CTCL), subtypes mycosis fungoides
Cohort 3: PTCL (recruitment to this cohort stopped March 2021)
(MF) and Sézary syndrome (SS)
Only PTCL patients with histologically or cytologically confirmed Peripheral T-Cell
Only CTCL patients with histologically or cytologically confirmed MF or SS with stage
Lymphoma - Not Otherwise Specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma
IIb to IVb disease based on modified ISCL/EORTC staging
(AITL), or Anaplastic Large Cell Lymphoma (ALCL)
At least one line and a maximum of four prior standard systemic therapies and no other
At least one line of prior combination therapy and no other standard therapy available
standard therapy available with proven clinical benefit
with proven clinical benefit
Cohort 5: PTCL (Recruitment to this cohort stopped March 2021)
Eligibility criteria for sub study
Diagnosis of relapsed or refractory lymphoma, including Diffuse large B cell lymphoma who
failed at least 2 lines of prior systemic therapy, Hodgkin lymphoma who failed at least 3
lines of prior systemic therapy, follicular lymphoma grade 1-3a, marginal zone lymphoma and
mantle cell lymphoma who failed at least 2 lines of prior systemic lines of prior therapy
T cell lymphoma (including PTCL, CTCL) who failed at least 2 lines of prior systemic
therapy for which there are no available therapies. Patients with bulky disease and
Multiple Myeloma patients are excluded from this sub study

Exclusion Criteria

Patient who had a hematologic malignancy that has transformed
Patients with any central nervous system involvement
Any patient who has relapsed within 100 days of stem cell infusion following an
Patients with corrected QT (QTc) interval (Fridericia's formula) > 450 msec
allogenic or an autologous bone marrow transplant
Patients who are on treatment with drugs known to prolong the QT/QTc interval
Any serious medical condition that interferes with adherence to study procedures
Pregnant or breast feeding females
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
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
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
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
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
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
mg PO QD or less seven (7) days prior to study drug administration are allowed
Patients on Valproic Acid for any indication (epilepsy, mood disorder) must be
excluded from the trial
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