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

Mundipharma Research Limited18 个研究点分布在 7 个国家目标入组 106 人开始时间: 2016年4月14日最近更新: 2024年7月25日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: Mundipharma Research Limited
入组人数: 106
试验地点: 18
主要终点: Overall response rate

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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

详细描述

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.

This study is a multi-centre, open-label phase 1 study of single agent EDO-S101 in subjects with relapsed/refractory haematological malignancies and for whom no other therapies are available.

The study consists of 2 stages and 1 sub-study:

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.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Single Group
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Patient willing and able to sign an informed consent.
•Patients age ≥18 years at signing the informed consent.
•Life expectancy > 3 months.
•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 ≥100,000 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 at least at the lowest limit of normal (LLN) at baseline(before every IMP administration; if it is below LNN, (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 (Recruitment to this cohort stopped Dec 2021)
•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
•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)
•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).
•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: 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.

排除标准

•Patients with any central nervous system involvement.
•Patient who had a hematologic malignancy that has transformed.
•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 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
•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 .