Evaluation of Safety, Pharmacokinetics, and Efficacy of AB8939 and Azacitidine in Patients with Relapsed/Refractory Acute Myeloid Leukemia
- Trial ID
- 2024-516641-39-00
- Protocol
- AB18001
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to define the **safety** and tolerability of AB8939 in patients with refractory or relapsed **Acute Myeloid Leukemia** (AML) and Myelodysplastic Syndromes (MDS). This will be achieved by determining the dose-limiting toxicities, the maximum tolerated dose (MTD), and the recommended dose for dose expansion study. Understanding the safety profile is crucial for ensuring patient safety and optimizing therapeutic dosing in this patient population.
Secondary objectives include:
- To determine the **pharmacokinetics** profile in function of dose, which is essential for understanding the drug's absorption, distribution, metabolism, and excretion characteristics.
- To assess early **efficacy**, providing preliminary insights into the therapeutic potential of AB8939 in the target patient group.
Participants
The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** (AML) or myelodysplastic syndrome (MDS), focusing on those with refractory or relapsed conditions. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ function and must not have severe dysfunctions in the heart, lungs, liver, kidneys, or nervous system, nor any immune deficiencies. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria emphasize the ability to understand and consent to the study, as well as compliance with study procedures, including bone marrow biopsies. Participants must not be eligible for hematopoietic stem cell transplantation at the time of inclusion and should have recovered to a maximum of Grade 1 toxicity from prior therapies. The interval from prior treatment to the administration of AB8939 should be at least 14 days, provided there is no rapidly progressing disease. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, pharmacokinetics, and efficacy of the investigational drug AB8939 in patients with relapsed or refractory **Acute Myeloid Leukemia** (AML). This study is structured as a Phase 1/2 trial, employing a randomized, double-blind, and controlled methodology to ensure robust and unbiased results. The trial is expected to span from June 28, 2022, to December 30, 2025, encompassing both the recruitment and treatment phases.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented diagnosis of AML or myelodysplastic syndrome (MDS), and the ability to comply with study procedures. Following successful screening, participants will enter the treatment phase, which involves daily intravenous administration of AB8939. The primary endpoint is to assess the rate of dose-limiting toxicity, while secondary endpoints include evaluating the rate and duration of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and other response rates.
Study visits will include regular follow-up assessments to monitor safety, efficacy, and pharmacokinetic parameters. These visits are crucial for determining the maximum tolerated dose and the recommended dose for further studies. The end-of-study visit will conclude the participant's involvement, summarizing the overall treatment outcomes and any adverse events experienced.
Participant involvement is expected to last until the end of the study unless early termination is warranted. Conditions for early termination include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the therapeutic potential of AB8939 for patients with limited treatment options due to relapsed or refractory AML.
Treatment
The clinical trial involves the administration of **AB8939**, an investigational medicinal product formulated as a **powder for injection**. The active substance in AB8939 is **1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one**, a chemical compound developed by AB Science. This experimental medication is administered via **intravenous injection**. The study aims to evaluate the safety, pharmacokinetics, and efficacy of daily intravenous administration of AB8939 in patients with relapsed or refractory **acute myeloid leukemia** (AML). The trial seeks to determine the dose-limiting toxicities, maximum tolerated dose, and recommended dose for further studies. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to AB8939, the study includes the use of **Vidaza**, a commercially available antineoplastic agent. Vidaza is provided as a **25 mg/ml powder for suspension for injection**, with **azacitidine** as its active substance. This medication, manufactured by Bristol-Myers Squibb Pharma EEIG, can be administered either **intravenously (IV)** or **subcutaneously (SC)**. Vidaza serves as a comparator treatment in the study, allowing for the assessment of AB8939's efficacy and safety relative to an established therapeutic option. The administration of Vidaza follows standard dosing protocols, and participant adherence to the treatment regimen will be closely monitored to ensure accurate data collection and analysis.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the rate of dose-limiting toxicity (DLT), which will help determine the safety and tolerability of the investigational product, AB8939, in patients with **acute myeloid leukemia (AML)** or myelodysplastic syndrome (MDS). Secondary endpoints include the rate and duration of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and complete remission with minimal residual disease (CRMRD). Additionally, the trial will evaluate the rate of partial remission (PR), overall response rate (ORR), hematologic improvement (HI), and marrow leukemia-free state (MLFS).
Pharmacokinetic (PK) parameters such as Tmax, Cmax, AUC0-t, AUC0-inf, t1/2, Cl, and Vd will be measured after the first administration to six patients at a specific dose level. The response rate will also be assessed based on the subtype of leukemia and classification on risk-status, utilizing the World Health Organization (WHO) classification, National Comprehensive Cancer Network (NCCN) guidelines, and European LeukemiaNet (ELN) risk stratification by genetics, including caryotype and molecular studies by targeted next-generation sequencing (NGS).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with documented diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) based on the last version of the World Health Organization classification.
- Patients must have adequate organ function without severe heart, lung, liver, kidney or nervous system dysfunction or immune deficiency
- In the absence of rapidly progressing disease, the interval from prior treatment to time of AB8939 administration should be at least 14 days.
- Patients are able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
- Adequate recovery, to a maximum of Grade 1 (CTCAE V5.0) from toxicity of prior therapy.
- Patients are able and willing to comply with trial procedures as per protocol, including bone marrow biopsies
- AML patients in second, third, fourth, or fifth line of treatment, if they were eligible to high dose chemotherapy in first line. Or AML patients in second line of treatment, if they were not eligible to high dose chemotherapy in first line. Or MDS patients in second, third, fourth, or fifth line of treatment and with high risk at prognostic based on the IPSS-R scoring system.
- All patients should have white blood cell count <25 × 109 /l prior to initiation of venetoclax and cytoreduction prior to treatment may be required
- Patients must be expected to complete the treatment period, in the opinion of the investigator.
- Male or non-pregnant female ≥ 18 years old at the time of signing the informed consent.
- ECOG performance status ≤ 1
- Patients not eligible to hematopoietic stem cell transplantation (HSCT) at the time of inclusion
Exclusion Criteria
- Patients eligible to hematopoietic stem cell transplantation (HSCT) at the time of inclusion
- Patients with clinically active CNS leukemia
- Patients with other active malignancies are ineligible unless they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence or progression of that malignancy
- Women who are lactating/breastfeeding or who plan to breastfeed while on trial
- Patients with major surgery within 28 days prior to the first administration of AB8939
- Patients with radiation therapy within 28 days prior to the first administration of AB8939
- Patients with uncontrolled hypertension e.g. SBP/DBP >149/90 mmHg despite two anti-hypertensive therapy
- Patients with history or evidence of neuromuscular disease such as amyotrophic lateral sclerosis, muscular dystrophy, polymyositis, myasthenia gravis, dermatomyositis, sarcopenia,
- Patients with history or evidence of cardiovascular disease such as stroke, ischemic heart disease (myocardial infarction, acute coronary syndrome, unstable angina), heart failure (EF < 50%), conduction disorders (Second degree or third-degree atrioventricular block not successfully treated with a pacemaker, Bi-fascicular block), uncontrolled arrythmia, abnormal QT interval (QTcF > 450 ms for male and >470 ms for female patients), history of torsades de pointes, pericarditis, valvular disease that are not well-controlled
- Patients with history or evidence of renal disease such as severe renal failure defined as creatinine clearance < 30 ml/min,
- Patients with history or evidence of CNS disease such as epilepsy, Alzheimer's and other dementias, strokes, migraine and other headaches possibly related to brain tumor or metastasis, multiple sclerosis, Parkinson's disease, neurological infections, brain tumors, sequellae of head injuries and disorders caused by malnutrition
- Patients with diabetes that are not well-controlled by two oral anti-diabetic drugs or insulin with Fasting Blood Glycemia > 110mg/dl and /or HbA1c >7%
- Patients with vitamin B12 deficiency, or alcohol addiction
- Women with a positive pregnancy test
- Patients with positive test for active AIDS (HIV1-2 test), Hepatitis B (antigene HBs), C (PCR positive), and tuberculosis
- Patients with white blood cells count or circulating blasts ≥ 20,000 cells/µL with hydroxyurea at screening
- Patients with AST and or ALT ≥ 2.5 ULN,Total bilirubin level > 1.5 ULN (except in case of Gilbert’s syndrome but within the limit of 3 x ULN) Serum creatinine ≥ 1.5 ULN and Albumin <30g/l (as AB8939 has a strong plasma protein binding)
- Men and women of reproductive potential who are unwilling to practice a highly effective method(s) of birth control while on study and 6months for women and 3 months for men; after receiving the last dose of study drug
- Women planning to become pregnant while on study and 6months after receiving the last dose of study drug
- Patients under psychiatric or, protected by law under guardianship or curatorship, or in emergency situations or, prisoners or, without National Health Insurance
- Patients diagnosed with acute promyelocytic leukemia (M3)
- Patients eligible to standard of care
- Patients with HSCT within 100 days prior to the first administration of AB8939
- Patients who are receiving any other investigational administered with the intention to treat their malignancy within 2 weeks from the last dose prior to entering the study, with the exception of hydroxyurea.
- Patients likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge
- Patients with known toxicity to venetoclax and/or to azacitidine who intend to participate in steps involving either venetoclax or/and azacitidine
- Patients who have received prior standard treatment within 2 weeks or those who have not recovered from adverse events due to treatment administered more than 2 weeks earlier
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 28 Jun 2022 | 10 |
 Germany | Not Yet Recruiting | 28 Jun 2022 | 10 |
 Greece | Not Yet Recruiting | 28 Jun 2022 | 15 |
 Spain | Not Yet Recruiting | 28 Jun 2022 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AB8939 | Test | POWDER FOR INJECTION | INTRAVENOUS INJECTION | — | — | PRD10492693 |
Vidaza 25 mg/ml powder for suspension for injection | Test | POWDER FOR SUSPENSION FOR INJECTION | INTRAVENOUS (IV) OR SUBCUTANEOUS (SC) | — | — | PRD9244549 |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD11643495 |