Phase 1/2a Open-Label Study of MP0533 in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndromes
- Trial ID
- 2023-505259-39-00
- Protocol
- MP0533-CP101
- Sponsor
- Molecular Partners AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to investigate **MP0533** as a monotherapy in patients with relapsed or refractory **Acute Myeloid Leukemia (AML)** and **Myelodysplastic Syndrome (MDS)**/AML. The study aims to determine the safety and tolerability of MP0533, define the recommended phase 2 dose regimen (RP2D-R) and/or the maximum tolerated dose-regimen (MTD-R) during phase 1, and evaluate the preliminary anti-leukemic activity, which is a primary objective for phase 2a. These objectives are clinically relevant as they address the need for effective treatment options in patients with limited therapeutic alternatives due to the aggressive nature of these hematological malignancies.
Secondary objectives include: - Evaluating the preliminary anti-leukemic activity in phase 1, - Characterizing the pharmacokinetics (PK) of MP0533. These secondary objectives are crucial for understanding the drug's efficacy and behavior in the body, which can inform dosing strategies and potential therapeutic benefits.
Participants
The clinical trial involves a total of **28 participants** diagnosed with **Myelodysplastic Syndrome (MDS)** or **Acute Myeloid Leukemia (AML)**. The study population includes both male and female subjects, aged 18 years and older, with a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale. Participants were selected based on their diagnosis of relapsed or refractory AML or MDS/AML, as per the European LeukemiaNet (ELN) recommendations of 2022. The trial includes individuals with an anticipated life expectancy of at least 12 weeks and adequate renal and hepatic function. Participants are required to have a white blood count of 15G/L or less on the day of trial drug infusion, with prior hydroxyurea use permitted. The study population is characterized by the use of highly effective contraception for females of childbearing potential and for men. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational treatment's safety and efficacy across a diverse group of patients.
Plans and Procedures
The clinical trial is designed as a **phase 1/2a**, first-in-human, open-label, multicenter, dose escalation study to evaluate the investigational product **MP0533** in patients diagnosed with **acute myeloid leukemia (AML)** or **myelodysplastic syndrome (MDS)**. The primary objectives of the trial are to determine the safety and tolerability of MP0533, define the recommended phase 2 dose regimen (RP2D-R) and/or the maximum tolerated dose-regimen (MTD-R) in phase 1, and evaluate the preliminary anti-leukemic activity in phase 2a. The trial is expected to run until December 31, 2030, with recruitment having commenced on April 3, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of relapsed/refractory AML or MDS/AML, age of 18 years or older, and adequate renal and hepatic function. Following the screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, tolerability, and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, assessing the overall response rate and any adverse events experienced during the trial.
The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will assess primary endpoints such as the incidence of cytokine release syndrome (CRS) and non-CRS dose-limiting toxicities (DLTs) during the first cycle of treatment, as well as secondary endpoints like pharmacokinetic parameters and overall survival in phase 2a. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of **Venclyxto** 100 mg film-coated tablets, which contain the active substance **venetoclax**. This medication is provided in the form of film-coated tablets and is administered orally. The frequency and specific dosage regimen are determined based on the study protocol, with careful monitoring of participant compliance to ensure adherence to the prescribed dosing schedule. **Venetoclax** is a chemical compound, and its administration is intended to evaluate its effects in the context of the trial.
Another treatment used in the study is **Vidaza** 25 mg/ml powder for suspension for injection, which contains the active substance **azacitidine**. This medication is prepared as a suspension for injection and can be administered via intravenous injection or infusion. The dosing schedule and frequency are specified in the study protocol, with compliance monitoring to ensure accurate administration. **Azacitidine** is a chemical compound, and its role in the trial is to serve as a comparator treatment to assess its efficacy and safety alongside other investigational products.
The investigational product **MP0533** is also utilized in this clinical trial. It is provided as a solution for infusion and contains a combination of active substances: **sodium dihydrogen phosphate dihydrate**, **polysorbate 20**, and **sodium chloride**. The administration route is intravenous, and the dosing regimen is outlined in the study protocol. Participant compliance is monitored to ensure proper adherence to the infusion schedule. The combination of these substances is intended to explore their potential therapeutic effects in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Efficacy
Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the incidence of cytokine release syndrome (CRS) and non-CRS dose-limiting toxicities (DLTs) during the first cycle of treatment in phase 1, as well as the type, incidence, and severity of adverse events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Additionally, changes in laboratory safety parameters and vital signs will be monitored. For phase 2a, the overall response rate (ORR) will be evaluated based on the best overall response, including complete remission, complete remission with partial hematological recovery (CRh), complete remission with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR) according to the European LeukemiaNet (ELN) response criteria 2022.
Secondary endpoints will focus on pharmacokinetic (PK) parameters such as maximum concentration (Cmax), time at maximum concentration (Tmax), minimal serum concentration (Cmin), area under the concentration-time curve (AUC), total clearance (CL), volume of distribution (Vd), and half-life (t1/2). The study will also assess different levels of CR, CRh, CRi, MLFS, and PR according to the ELN response criteria 2022, both separately and pooled. Additional secondary endpoints include event-free survival (EFS), duration of response (DoR), overall survival (OS) in phase 2a, the number of patients proceeding to stem cell transplantation, and transfusion-independence (TI).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has signed and dated written informed consent prior to performing any study procedure, including screening
- Diagnosis of relapsed/refractory AML or relapsed/refractory MDS/AML according to the ELN recommendation 2022
- Age ≥18 years old on the day of signing informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2
- Anticipated life expectancy ≥ 12 weeks by investigator judgement
- Adequate renal and hepatic function: a. Creatinine clearance > 40 mL/min on the basis of Cockcroft-Gault glomerular filtration rate estimation, unless considered AML- or MDS-related b. Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML- or MDS-related or due to Gilbert’s syndrome c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN, unless considered AML- or MDS-related
- White blood count (WBC) ≤ 15G/L at day of trial drug infusion (prior hydroxyurea allowed)
- Is using highly effective contraception, for females of childbearing potential (FCBP) and for men.
Exclusion Criteria
- Mixed phenotype acute leukemia
- Allogeneic HCT within the last 3 months prior to start of trial medication and/or eligibility for standard 2nd line of targeted therapy, like gilteritinib for FLT3 mutated AML, unless this therapeutic option has already been given and proven ineffective (patient relapsed or resistant to), or contraindicated, or confounding mutations exist, or there is a lack of access to this recommended therapy.
- Known hypersensitivity to any of the excipients of the investigational medicinal product (IMP), i.e. finished MP0533 drug
- Any condition that, in the opinion of the investigator, would interfere with evaluation of the IMP or interpretation of the patient’s data
- Unable or unwilling to comply with all study requirements for clinical visits, examinations, tests and procedures, and contraception requirements
- Patient deprived of liberty by a judicial or administrative decision, patient admitted to a social institution or who is under a measure of legal protection, patient hospitalized without consent or who is in an emergency
- Active GvHD requiring immune-suppressive therapy (other than prednisone (or equivalent) ≤ 10mg/d)
- Use of immunosuppressive drugs (other than prednisone (or equivalent) ≤10mg/d) in the past 4 weeks
- Clinical signs of AML in the central nervous system
- Major surgery within 28 days prior to start of study medication
- Other malignancy requiring active therapy, but adjuvant endocrine therapy is allowed
- Left ventricular ejection fraction of < 50% on echocardiographic exam at screening
- Any uncontrolled active infection
- Treatment with investigational agents or agents targeting CD33, CD123 or CD70 within 4 weeks or five times the half-life of the agent, whichever is longer, prior to start of trial medication
- History or evidence of clinically significant cardiovascular disease defined as at least one of the following criteria: Evidence of poorly controlled arterial hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg); Myocardial infarction or unstable angina pectoris within 6 months before screening; Heart failure (New York Heart Association Class III or IV); Any cardiac arrhythmia that is not well controlled; QT corrected (QTc) prolongation ≥ Grade 2 (> 480 ms) at screening measured on 2 separate electrocardiograms (ECG) at least 10 minutes apart; Clinically significant valvular heart disease
- Pulmonary disease with clinically relevant hypoxia (need for continuous oxygen inhalation)
- Known Human Immunodeficiency Virus (HIV)-infected patients who are healthy and have a low risk of Acquired Immunodeficiency Syndrome (AIDS)-related outcomes are eligible, if: No history of AIDS-defining opportunistic infection within past 12 months; Patient agrees to concomitant antiretroviral therapy (ART) if not currently on ART, is on ART for ˃ 4 weeks and has a HIV viral load ˂ 400 copies/mL
- Active hepatitis.
- Any vaccines within 28 days before first study drug administration
- History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥ 2 years before screening and of relatively low potential risk for recurrence; Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of residual disease; Adequately treated carcinoma in situ without evidence of disease; Cancer patients with incidental histologic findings of prostate cancer that, in the opinion of the investigator, is not deemed to require active therapy may be eligible, pending discussion and approval by the Sponsor
- Concurrent enrollment in another clinical trial, unless it is an observational (noninterventional) study or it is the follow-up period of an interventional study
- Patients with favorable AML mutations according to ELN recommendation 2022 and 2024.
- More than 2 prior lines of anti-leukemic therapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 03 Apr 2023 | 83 |
 Lithuania | Not Recruiting | 03 Apr 2023 | 55 |
 The Netherlands | Not Recruiting | 03 Apr 2023 | — |
| Netherlands | — | — | 83 |
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 |
|---|---|---|---|---|---|---|
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD11643495 |
MP0533 | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9944319 |
Vidaza 25 mg/ml powder for suspension for injection | Test | POWDER FOR SUSPENSION FOR INJECTION | IV INJECTION, IV INFUSION | — | — | PRD9244549 |