Etude : EDO-S101-1001 / Cohorte 2: lymphome de Hodgkin



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Acronyme / Nom
Situation thérapeutique
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme / Nom : EDO-S101-1001 / Cohorte 2: lymphome de Hodgkin

Situation thérapeutique : Induction

Traitement : Chimiothérapie

Type d'étude : Ciblage moléculaire / Innovation thérapeutique

Dernière MÀJ : 15/01/2021
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : Étude de phase 1 visant à évaluer l'innocuité, les profils pharmacocinétiques et l'efficacité de l'EDO-S101, une molécule de fusion HDACi alcoylante de première classe, dans les hémopathies malignes récidivantes ou réfractaires

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C81 - Lymphome de Hodgkin
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : STUDY DESIGN:
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.


STUDY ARM:
- 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


CURRENT PRIMARY OUTCOME:
- Overall response rate [ Time Frame: 10-20 months from beginning of stage 2 ]
- Clinical benefit rate by cohort [ Time Frame: 10-20 months from beginning of stage 2 ]
- 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

CURRENT SECONDARY OUTCOMES:
- Time to objective response [ Time Frame: 10-20 months after beginning stage 2 ]
- Duration of response [ Time Frame: 10-20 months after beginning stage 2 ]
- Progression free survival (PFS) [ Time Frame: 32-36 months after beginning stage 2 ]
- Overall Survival (OS) [ Time Frame: 32-36 months after beginning stage 2 ]
- Maximum Plasma Concentration (Cmax) [ Time Frame: 10-20 months after beginning stage 2 ]
- Time to Reach Maximum Concentration (Tmax) [ Time Frame: 10-20 months after beginning stage 2 ]
- Time taken for the plasma concentration to fall by half its original value (t1/2) [ Time Frame: 10-20 months after beginning stage 2 ]
- Area Under Curve (AUC) [ Time Frame: 10-20 months after beginning stage 2 ]
- QT (QTc) analysis [ Time Frame: 10-20 months after beginning stage 2 ]
- 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 ]

Phase : I

Stade : NA

Rechute, Réfractaire
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : - Execute 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.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤2
- Absolute Neutrophil Count >1,000 µL
- Platelets ≥75,000 µL
- Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of normal (ULN).
- Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.
- Creatinine ≤1.5 x ULN.
- Serum potassium and magnesium within normal range at baseline (supplementation is permissible).
- 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
- 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
- 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)
- 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).
- 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)
- Only CTCL patients with histologically or cytologically confirmed MF or SS with stage IIb to IVb disease based on modified ISCL/EORTC staging.
- 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)
- 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.

Critères de non-inclusion : - Patients with any central nervous system involvement.
- Diagnosis of acute leukemia or any patient that has been treated with fludarabine.
- Any patient who has relapsed within 100 days of stem cell infusion following an allogenic or an autologous bone marrow transplant.
- Patients with corrected QT (QTc) interval (Fridericia's formula) > 450 msec.
- 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.
- 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.
- Pregnant or breast feeding females.
- 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 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.
- 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 10 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 or must stop using the medication and have a wash out period of 3.5 days prior to first dose of tinostamustine (C1D1)
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT02576496
Promoteur :
Mundipharma Research Ltd
Type de sponsor : Industriel
UK
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Institut d'Hématologie Bas-Normand (IHBN) - Avenue de la Cote de Nacre - 14000 CAEN

Investigateur :
Gandhi Laurent DAMAJ

TEC / ARC / IDE :
Véronique ABONNET
abonnet-v@
chu-caen.fr

Statut de l'essai : OUVERT

MAJ : 01/12/2020