Phase II Multicenter Randomized Trial of WT1 mRNA-Electroporated Dendritic Cell Vaccination for Relapse Prevention in Adult Acute Myeloid Leukemia

Trial ID: 2024-515292-35-00
Protocol: WIDEA
Sponsor: Universitair Ziekenhuis Antwerpen

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Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this study is to determine the clinical efficacy of **WT1 mRNA-electroporated dendritic cell (DC) vaccination** as a post-remission strategy to prevent relapse and prolong overall survival in adult patients with **Acute Myeloid Leukemia (AML)**. This is clinically relevant as it addresses the critical need for effective post-remission therapies in AML, aiming to reduce relapse rates and improve long-term patient outcomes.

Secondary objectives include:

Assessing the relapse rate and relapse-free survival two years post-morphological complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following bone marrow examination.
Determining the efficacy of the DC vaccine strategy in controlling or eradicating minimal residual disease (MRD) by monitoring WT1 transcript levels in peripheral blood.
Investigating the immunogenicity of the WT1 mRNA-electroporated DC vaccines and their capability to induce anti-leukemic immune responses in vivo.
Evaluating changes in general and disease-specific quality of life using EQ-5D-5L and QLQ-C30 questionnaires at regular intervals.

Participants

The clinical trial focuses on adult participants diagnosed with **Acute Myeloid Leukemia** (AML), specifically targeting those at a very high risk of relapse. The study population includes both male and female subjects aged 18 years and older. Participants are selected based on their diagnosis according to the 2008 World Health Organization criteria, excluding certain subtypes and secondary AML cases unless specific treatments were administered. The trial involves individuals who have completed intensive or low-intensity chemotherapy, achieving either morphological complete remission or complete remission with incomplete blood recovery. Participants must have a WHO performance status of grade 0, 1, or 2 at enrollment. The trial also considers the absence of any conditions that could impede compliance with the study protocol. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is a multicenter, two-group **randomized**, open-label, phase II study designed to evaluate the efficacy of autologous WT1 mRNA-electroporated dendritic cell vaccination as a post-remission strategy to prevent relapse in adult patients with **acute myeloid leukemia** (AML). The trial aims to determine the clinical efficacy of this vaccination in prolonging overall survival. The study is expected to run from June 24, 2013, to November 30, 2028, with participants involved for a maximum treatment period of 97 days. The trial involves intradermal injection of the WT1 mRNA DC product, with a maximum daily dose of 10,000,000 units.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as diagnosis of AML, age, risk of relapse, and completion of specific chemotherapy regimens. The inclusion visit will also assess the WHO performance status and ensure the absence of conditions that could hinder compliance with the study protocol. Follow-up visits will be scheduled to monitor clinical response, including overall survival, relapse-free survival, and relapse rate at two years. Tumor marker levels and immune system activation will be assessed through peripheral blood samples, using quantitative real-time RT-PCR and flow cytometry, respectively. Patient-reported outcomes will be evaluated using EQ-5D-5L and QLQ-C30 questionnaires at regular intervals.

The end-of-study visit will conclude the participant's involvement, with final assessments of clinical response and quality of life. Participants may be terminated early from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial's primary endpoint is overall survival, with secondary endpoints including clinical response analysis, molecular response, immune system activation, and patient-reported outcomes. The study is not classified as low intervention and does not involve a **double-blind** design, allowing for open-label administration of the investigational product.

Treatment

The clinical trial involves the administration of **WT1 mRNA DC**, an experimental medication designed for the treatment of adult patients with acute myeloid leukemia (AML). This investigational product is formulated as an **injection** and is administered via **intradermal injection**. The active substance, **WT1 mRNA DC**, is a structurally diverse substance categorized under cell therapy. It consists of monocyte-derived dendritic cells that have been electroporated with Wilms' Tumor 1 mRNA. The maximum daily dose is set at 10,000,000 units, with the same amount being the maximum total dose permissible over the course of the treatment. The maximum treatment period is 97 days. The product is not a pediatric formulation and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial's primary objective is to evaluate the clinical efficacy of the WT1 mRNA-electroporated dendritic cell vaccination as a post-remission strategy to prevent relapse and prolong overall survival in adult AML patients. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

The efficacy of the WT1 mRNA-electroporated dendritic cell (DC) vaccination in preventing relapse and prolonging overall survival in adult patients with acute myeloid leukemia (AML) will be assessed through a series of primary and secondary endpoints. The primary endpoint is overall survival, which will be measured to determine the clinical efficacy of the vaccination as a post-remission strategy.

Secondary endpoints include clinical response analysis, which will be conducted on all efficacy-evaluable patients according to the 'Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia'. This analysis will focus on relapse-free survival and relapse rate at two years. Additionally, tumor marker levels will be monitored in peripheral blood by measuring WT1 mRNA levels using specific primers and quantitative real-time RT-PCR, with molecular response defined as the normalization of WT1 transcript levels below background.

Further secondary endpoints involve monitoring the activation of the immune system. Peripheral blood samples will be examined using flow cytometry to assess functional WT1-specific T cell responses, WT1-specific CD8+ T cells, and changes in lymphocyte subset distribution and activation state. Patient-reported outcomes will also be evaluated to assess changes in general and disease-specific quality of life using EQ-5D-5L and QLQ-C30 questionnaires at regular time points.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis of acute myeloid leukemia (AML) according to the 2008 criteria of the World Health Organization (WHO): A) All French-American-British (FAB) subtypes (except for M3 (acute promyelocytic leukemia)) B) All cases of de novo AML or secondary AML with ≥20 % blasts in peripheral blood and/or bone marrow (except for AML secondary to myeloproliferative neoplasms (MPN) and AML secondary to exposure of leukemogenic agents (therapy-related (t)-AML) unless treated with CPX-351 chemotherapy or hypomethylating agents combined with venetoclax)
Adult (≥18 years) at very high risk of relapse according to A) Age ≥60 years, and/or B) Adverse biological features (e.g. adverse cytogenetics, adverse morphological features, adverse molecular features, hyperleukocytosis (>100000 cells/µL)), and C) Ineligible for or unwilling to receive hematopoietic stem cell transplantation
Completion of one of the following treatment options: I) Intensive chemotherapy: [(1) At least one cycle of induction chemotherapy and one cycle of consolidation chemotherapy (low-dose cytarabine as consolidation therapy is allowed) OR (2) One to two cycles of CPX-351 induction treatment and up to two cycles of CPX-351 consolidation treatment] OR II) Low-intensity chemotherapy: [(3) At least two cycles to maximum six cycles of hypomethylating agents (HMA) whether or not combined with venetoclax (VEN) OR (4) At least two cycles to maximum six cycles of low-dose cytarabine (LDAC) combined with venetoclax]; resulting in: A) Morphological complete remission (CR) (i.e. bone marrow blast count <5% with neutrophil count >1000 cells/µL and platelet count >100,000 cells/µL) OR B) Morphological complete remission with incomplete blood recovery (CRi) (i.e. bone marrow blast count <5% with neutrophil count <1000 cells/µL or platelet count <100,000 cells/µL. For the purpose of this study protocol, platelet count must be >50,000 cells/µL)
WHO performance status: grade 0,1 or 2 at the time of enrollment (For definition of performance status, see: http://www.ecog.org/general/perf_stat.html)
Absence of any psychological, familial, sociological, geographical or physical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before study entry

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Exclusion Criteria

Participation in any other interventional clinical trial during the study period
History or concomitant presence of any other malignancy, except for: A) Non-melanoma skin cancer B) Carcinoma in situ of the cervix C) Any other effectively treated malignancy that has been in remission for >5 years or that is highly likely to be cured at the time of enrollment
Known concomitant presence of any immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo
Concomitant use of systemic corticosteroids in immunosuppressive doses (>1 mg/kg/day of prednisone, or equivalent dose for other corticosteroid preparations) or any other immunosuppressive agent. A minimum of 4 weeks must have elapsed between the last dose of immunosuppressive therapy and the first vaccination. Topical corticosteroids are permitted, except if applied at the sites of DC injection
Pregnant or breast-feeding