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

Study Overview
=================
Brief Summary
-----------------
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 followed by a Regimen optimization part with an extension cohort.

Detailed Description
-----------------
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 followed by a Regimen optimization (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.

Official Title
-----------------
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.

Conditions
-----------------
Acute Myeloid Leukemia, Adult, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: ABD-3001
* Drug: ABD-3001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Exclusion Criteria: Patients with acute myeloid leukemia (AML) with Inv(16) MYH11-CBF 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 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 History of other malignancy in the last 12 months prior to study Visit 1 Other active solid tumor Patients taking medications that are known to prolong the QT interval 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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 followed by a Regimen optimization part with an extension cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Administration Dose (SAD) of ABD-3001<br>Dose escalation of 6 doses level using a 3+3 design. | Drug: ABD-3001<br>* Each patient will receive a single and fixed 4 hours-intravenous infusion dose of ABD-3001. 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.<br>* Other names: DIMATE;|
| Experimental: Multiple Administration Dose (MAD) of ABD-3001<br>Dose escalation of 3 doses level for a full cycle of treatment (28 days). | Drug: ABD-3001<br>* Based on PK data gathered during the SAD, a dose regimen optimization will be done using population Pharmacokinetic modelling in order to set the optimal frequency of infusion per week to achieve sustained exposition throughout treatment period. Based on this analysis, the Sponsor will, in accordance with the Safety review Committee, define the occurrence of infusion to 1, 2 or 3 times per week, during 4 weeks (28 days ± 3 days). Number of infusions given per week and dose increase between each dose will be set so that, whatever the initial dose used in the MAD part, total dose increase will never get above the MTD determined in the SAD part or a dose defined by the SRC, if no MTD is determined during the SAD part.<br>* Other names: DIMATE;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of the Maximum Tolerated Dose (MTD) | The primary endpoint is to assess the MTD by evaluation of incidence of patients who experienced Dose Limiting Toxicities (DLTs) assessed according to CTCAE v5.0. | 7 days for SAD part up to 2 months for MAD part. | 
| Recommendation of the dose for the Phase 2 (RP2D). | The recommendation for the Phase 2 dose will be determined using MTD, cumulative safety and signs of anti-leukemic activity, pharmacokinetic and pharmacodynamic characteristics. | 2 months for MAD part. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | 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. | 7 days for SAD part up to 2 months for MAD part. | 
| PK parameters assessment (Cmax) | Evaluation of maximum concentration (Cmax) of ABD-3001. | 7 days for SAD part up to 2 months for MAD part. | 
| PK parameters assessment (AUC) | Evaluation of Area Under the Curve (AUC) of ABD-3001. | 7 days for SAD part up to 2 months for MAD part. | 
| PK parameters assessment (Tmax) | Evaluation of time to maximum concentration (Tmax) of ABD-3001. | 7 days for SAD part up to 2 months for MAD part. | 
| PK parameters assessment (T1/2) | Evaluation of elimination half-life of ABD-3001. | 7 days for SAD part up to 2 months for MAD part. |