First-in-human Study Aiming to Characterize the Safety, Tolerability, Pharmacokinetic and Preliminary Signs of Activity of ABD-3001 in Refractory or Relapsed AML and High Risk MDS Adult Patients

Официальное название

First-In-Human, Open Label, Dose Escalation Study to Evaluate Safety, PK and PD of ABD-3001 As Monotherapy in Relapsed/Refractory Acute Myeloid Leukemia or High/Very-high Risk Myelodysplastic Syndromes Patients, Ineligible for Intensive or New Generation Targeted Therapy.

Обзор

This First In Human (FIH) study is a prospective, open-label, multicenter, Phase 1 study, with a dose escalation design, followed by an optimized design. It will consist in a Single Ascending Dose (SAD) part and a Multiple Ascending Dose (MAD) part.

Подробное описание

This FIH study combines, in patients with primary refractory or relapsed AML patients and in patients with high risk MDS a Single Ascending Dose (SAD) part (Part A) and a Multiple Ascending Dose (MAD) part (Part B).

The objective of the SAD phase is to explore a wide range of dose administered as a single and fixed 4-hours intravenous infusion in order to select a dose and a dosing frequency (determined using pharmacokinetic and pharmacodynamics parameters).

The objective of the MAD is to elucidate the pharmacokinetic (PK) and pharmacodynamics (PD) of multiple doses of ABD-3001. The dose levels and dosing intervals (i.e., time between consecutive doses) will be selected as those that are predicted to be safe from the SAD. Dose levels and dosing frequency will be derived from data obtained during the SAD.

Вмешательства

• Препарат ABD-3001
  Each patient will receive a fixed 4 hours-intravenous infusion dose of ABD-3001 once or twice a week. For SAD : The first dose of the first cohort will receive an estimated infusion dose of 18 mg/m² at Day 1. Subsequent cohorts will be given the following doses: 54 mg/m², 135 mg/m², 270 mg/m², 405 mg/m², 540 mg/m².
• Препарат ABD-3001
  For MAD : Based on all data gathered during the SAD including safety, PK and preliminary efficacy data, up to three doses were selected in accordance with the Safety review Committee (SRC). A dosage optimization analysis was performed at the end of the SAD cohort 6 using population pharmacokinetic modelling to set the optimal frequency of infusion per week for each selected dose to achieve sustained exposition throughout the treatment period. Based on this analysis, the Sponsor, in agreement wi

Первичные конечные точки

• SAD : Estimation of the Maximum Tolerated Dose (MTD) of ABD-3001 as well as the doses and frequencies to be explored during the MAD [Срок оценки: 7 days for SAD part]
• MAD : To evaluate the safety, tolerability and to define a recommended dose range for further trials. [Срок оценки: 3 months for MAD part.]

Вторичные конечные точки (12)

• SAD : To evaluate the overall safety and tolerability profile of ABD-3001 [Срок оценки: 7 days for SAD part]
• SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001 [Срок оценки: 7 days for SAD part]
• SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001 [Срок оценки: 7 days for SAD part]
• SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001 [Срок оценки: 7 days for SAD part]
• SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001 [Срок оценки: 7 days for SAD part]
• MAD : 1. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : 2. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : 3. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : 4. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : 1. To assess the pharmacodynamic (PD) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : 2. To assess the pharmacodynamic (PD) parameter of multiple administration of ABD-3001. [Срок оценки: 3 months for MAD part.]
• MAD : To evaluate the anti-leukemic activity as assessed by overall response rate (ORR: complete response [CR] + complete response with incomplete hematopoiesis [CRi] + morphologic leukemia-free state [MFLS] + partial response [PR]) [Срок оценки: 3 months for MAD part.]

Критерии участия

Критерии включения

• Patients with relapsed/refractory Acute Myeloid Leukemia (AML) after failing at least one therapy regimen and a salvage treatment or are not eligible for salvage treatment regimens including targeted therapy
• Patients with relapsed/refractory Myelodysplastic syndrome (MDS) ineligible for salvage treatment who are diagnosed high-risk and very high-risk using Revised International Prognostic Scoring System (IPSS-R) prognostic risk categorization
• Patients not eligible to alloSCT
• Negative blood or serum/urine pregnancy test

Критерии исключения

• Patients with acute myeloid leukemia (AML) with Inv(16) MYH11-CBF-Beta or t(8;21) AML-ETO RUNX1-RUNX1 or (PML/RARA) karyotype abnormalities and eligible to targeted therapies
• Participants with clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia
• Ongoing immunosuppressive treatment
• Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to study Visit 1
• Active infection requiring intravenous anti-infectious treatment during the screening period
• Life-threatening illnesses other than the studied one, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety or interfere with the patient's ability to comply with the study activities
• Anti-tumor therapy within 14 days of study Visit 1
• Prior participation in an interventional investigational clinical study (drug or medical device) within 21 days of study Visit 1
• Radiotherapy within 28 days prior to study Visit 1
• Current history of seropositivity to human immunodeficiency virus (HIV) or infection with active hepatitis C virus (HCV) or active hepatitis B virus (HBV) or active SARS-CoV-2 (Covid-19) or Syphilis, or Cytomegalovirus (CMV), or Epstein-Barr virus (EBV), or Human T-Lymphotropic Virus (HTLV1)
• History of other malignancy in the last 12 months prior to study Visit 1
• Other active solid tumor
• Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or Left Ventricular Ejection Fraction (LVEF) <50% attested by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days of C1D1 prior to study Visit 1 (Day 1, start of study therapy)
• Subjects with a history of myocardial infarction within the last 3 months prior to study Visit 1 (Day 1, start of study therapy)
• Subjects with heart-rate corrected QT (QTc) interval ≥450 ms or other factors that increase the risk of QT prolongation or arrhythmic events
• Major surgery within 4 weeks prior to study Visit 1 (Day 1, start of study therapy)
• Any condition deemed by the investigator to be likely to interfere with a subject's ability to participate in the clinical trial MAD specific exclusion criteria: Patients who have been part of SAD and have experienced a DLT.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 3 центра

• Hôpital de la Timone — Marseille
• Hôpital Saint-Louis — Paris
• Centre Hospitalier Lyon Sud — Pierre-Bénite

Публикации

• Venton G, Colle J, Tichadou A, Quessada J, Baier C, Labiad Y, Perez M, De Lassus L, Loosveld M, Arnoux I, Abbou N, Ceylan I, Martin G, Costello R. Reactive oxygen species and aldehyde dehydrogenase 1A as prognosis and theragnostic biomarker in acute myeloid leukaemia patients. J Cell Mol Med. 2024 Oct;28(19):e70011. doi: 10.1111/jcmm.70011. PMID 39392121

Идентификаторы

NCT: NCT05601726 · ABD3001CLIN1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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