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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
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.
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 with the SRC, defined 3 doses regimens that will be set up in parallel, with infusion of ABD-3001 once or twice a week during 3 cycles of 28 days.
Hôpital de la Timone
Marseille, France, France
RECRUITINGHôpital Saint-Louis
Paris, France, France
RECRUITINGCentre Hospitalier Lyon Sud
Pierre-Bénite, France, France
RECRUITINGSAD : Estimation of the Maximum Tolerated Dose (MTD) of ABD-3001 as well as the doses and frequencies to be explored during the MAD
The primary endpoint is to assess the recommended dose range to be tested during the MAD by evaluation of incidence of patients who experienced Dose Limiting Toxicities (DLTs). according to CTCAE v5.0. The recommendation for doses to be tested during the MAD will be determined using all available data, which will include Dose Limiting Toxicities (DLTs), MTD if it has been reached, and other toxicities, signs of anti-leukemic activity, pharmacokinetic and pharmacodynamic characteristics.
Time frame: 7 days for SAD part
MAD : To evaluate the safety, tolerability and to define a recommended dose range for further trials.
To assess the impact of ABD-3001 on safety and on its tolerability by evaluating: 1. Incidence of Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0 Nov. 27, 2017)), timing, seriousness, and relationship to ABD-3001 either observed by the investigator during physical examination, or reported spontaneously by the patient, 2. Incidence of laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0 Nov. 27, 2017), and timing.
Time frame: 3 months for MAD part.
SAD : To evaluate the overall safety and tolerability profile of ABD-3001
To assess the impact of ABD-3001 on safety and on its tolerability by evaluating: 1. Incidence of Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0 Nov. 27, 2017)), timing, seriousness, and relationship to ABD-3001 either observed by the investigator during physical examination, or reported spontaneously by the patient, 2. Incidence of laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0 Nov. 27, 2017), and timing,
Time frame: 7 days for SAD part
SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001
Maximum concentration (Cmax) of DIMATE and metabolites (CEY1410/H11)
Time frame: 7 days for SAD part
SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001
Time to maximum concentration (Tmax)
Time frame: 7 days for SAD part
SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001
Area Under the plasma Concentration versus time curve (AUC)
Time frame: 7 days for SAD part
SAD: To assess the pharmacokinetic (PK) parameters of ABD-3001
Elimination half-life.
Time frame: 7 days for SAD part
MAD : 1. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001.
PK parameter assessment: maximum concentration (Cmax) of DIMATE and metabolites (CEY1410/H11)
Time frame: 3 months for MAD part.
MAD : 2. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001.
PK parameter assessment: time to maximum concentration (Tmax)
Time frame: 3 months for MAD part.
MAD : 3. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001.
PK parameter assessment: Area Under the plasma Concentration versus time curve (AUC)
Time frame: 3 months for MAD part.
MAD : 4. To assess the pharmacokinetic (PK) parameter of multiple administration of ABD-3001.
PK parameter assessment: elimination half-life.
Time frame: 3 months for MAD part.
MAD : 1. To assess the pharmacodynamic (PD) parameter of multiple administration of ABD-3001.
PD parameter assessment: ALDH activity measurement in red blood cells
Time frame: 3 months for MAD part.
MAD : 2. To assess the pharmacodynamic (PD) parameter of multiple administration of ABD-3001.
PD parameter assessment: JUNK protein phosphorylation in plasma.
Time frame: 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])
To assess the potential preliminary evidence of anti-leukemia activity at each cycle using response criteria in AML without MRD assessment as defined by ELN 2022
Time frame: 3 months for MAD part.
MAD: To evaluate the duration of ORR.
To assess duration of ORR.
Time frame: 3 months for MAD part.
MAD: To evaluate Event free survival (EFS) and overall survival (OS) rates at 3-months and 6-months after the end of treatment
To assess the Event Free Survival and the Overall Survival as defined by ELN2022 until 6-months after end of treatment.
Time frame: 3 months for MAD part.
MAD: To assess the PRO-QoL during the treatment.
To assess the impact of ABD-3001 on quality of life according QLQ-C30 questionnaire at D1 of each cycle and at the end of treatment.
Time frame: 3 months for MAD part.
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