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

Sponsor
Mundipharma Research Limited (Industry)
Overall Status
Recruiting
CT.gov ID
NCT02576496
Collaborator
(none)
111
20
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81
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Study Details

Study Description

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.

Detailed Description

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.

Study Design

Study Type:
Interventional
Anticipated 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 :
Mar 1, 2016
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Overall response rate [10-20 months from beginning of stage 2]

    Determine overall response rate

  2. Clinical benefit rate by cohort [10-20 months from beginning of stage 2]

    Determine clinical benefit rate by cohort

  3. Safety of selected doses in expanded population [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 [10-20 months after beginning stage 2]

    Evaluate time to objective response by cohort

  2. Duration of response [10-20 months after beginning stage 2]

    Evaluate duration of response

  3. Progression free survival (PFS) [32-36 months after beginning stage 2]

    Determine time to progression free survival time for patients who received the RP2D

  4. Overall Survival (OS) [32-36 months after beginning stage 2]

    Determine the overall survival time for patients who received the RP2D

  5. Maximum Plasma Concentration (Cmax) [10-20 months after beginning stage 2]

    Determine Cmax using the PK population

  6. Time to Reach Maximum Concentration (Tmax) [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) [10-20 months after beginning stage 2]

    Determine t1/2 using the PK population

  8. Area Under Curve (AUC) [10-20 months after beginning stage 2]

    Determine area under the plasma drug concentration-time curve using the PK population

  9. QT (QTc) analysis [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 [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)

Other Outcome Measures

  1. Sub study cardiac safety [2 cycles]

    To characterize the effect of tinostamustine at a dose of 100 mg/m2 on cardiac repolarization (QTcF) and other ECG parameters

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
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 (Recruitment to this cohort stopped Dec 2021) 1. At least one line of prior systemic therapy and no other standard therapy available with proven clinical benefit.

Cohort 2: relapsed/refractory Hodgkin's lymphoma

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

Cohort 3: PTCL (recruitment to this cohort stopped March 2021)

  1. Only PTCL patients with histologically or cytologically confirmed Peripheral T-Cell Lymphoma - 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: 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:
  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 .

Contacts and Locations

Locations

Site City State Country Postal Code
1 Mayo Clinic Phoenix Arizona United States 85054
2 Mayo Clinic Cancer Center Jacksonville Florida United States 32224
3 Mayo Clinic Cancer Center Rochester Minnesota United States 55905
4 Columbia University Medical Center New York New York United States 10019
5 The University of Texas MDACC Houston Texas United States 77030
6 CHU de Caen Caen France CS 3001
7 CHU ESTAING Service de thérapie Cellulaire et hématologique Clinique Clermont Ferrand France 63000
8 CHU Lille Service des Maladies du Sang Lille France 59037
9 CHU de Nantes, Hotel Dieu Nantes France 44093
10 Hopital Haut Leveque Pessac France 33604
11 Centre hospitalier Lyon Sud Pierre Bénite France 69495
12 University Hospital of Ulm, Department of Internal Medicine III Ulm Germany 89081
13 Institute of Hematology "L. A. Seràgnoli", University of Bologna Bologna Italy 40138
14 National Cancer Institute, Fondazione 'G. Pascale' Naples Italy I-80131
15 VU medisch centrum Amsterdam Netherlands 1081 HV
16 Erasmus MC Rotterdam Netherlands 3015 GD
17 Institut Català d'Oncologia de Barcelona Hospitalet de Llobregat Barcelona Spain 08908
18 Hospital Universitario de Salamanca Salamanca Spain 37007
19 Hospital Universitario Marqués de Valdecilla Santander Spain 39008
20 Kantonsspital St.Gallen St.Gallen Switzerland 9007

Sponsors and Collaborators

  • Mundipharma Research Limited

Investigators

  • Principal Investigator: Pier L Zinzani, MD,PhD, University of Bologna Medical Center, Bologna

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Mundipharma Research Limited
ClinicalTrials.gov Identifier:
NCT02576496
Other Study ID Numbers:
  • EDO-S101-1001
First Posted:
Oct 15, 2015
Last Update Posted:
Apr 20, 2022
Last Verified:
Apr 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Mundipharma Research Limited
Additional relevant MeSH terms:

Study Results

No Results Posted as of Apr 20, 2022