Phase II Study on Efficacy and Safety of Tagraxofusp and Venetoclax in Treatment-Naive Blastic Plasmacytoid Dendritic Cell Neoplasm Patients

The primary objective of this study is to evaluate the **efficacy** of the combination of tagraxofusp and venetoclax (TAGVEN) in treatment-naive adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). This is measured by the rate of composite complete remission (cCR), which includes complete remission (CR), complete remission with incomplete marrow recovery (Cri), or complete response with minimal residual skin abnormality (CRc[clinical]). The assessment is based on the European Leukemia Net 2022 definitions for acute myeloid leukemia (AML) and adapted for BPDCN, with a focus on achieving a marked clearance of ≥ 75% of skin lesions and a complete metabolic response after three cycles of the combination therapy. This objective is clinically relevant as it aims to establish an effective treatment regimen for a rare and aggressive hematologic malignancy.

Secondary objectives include: - Objective response rate (ORR) defined as cCR plus partial response (PR) - Safety profile of the tagraxofusp and venetoclax combination - Incidence of Minimal Residual Disease (MRD) negative responses measured by flow cytometry with a sensitivity of 0.1% - Progression-free survival (PFS) - Relapse-free survival (RFS) - Duration of response (DOR) - Overall survival (OS) - Number of patients bridged to allogeneic transplantation - Possible predictors of response with respect to cytogenetics and molecular status.

The clinical trial involves adult participants diagnosed with **blastic plasmacytoid dendritic cell neoplasms** (BPDCN) who have not received prior treatment. The study population includes both male and female subjects aged over 18 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of less than 3, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. They must also demonstrate adequate renal, cardiac, and liver function, as well as an albumin level of at least 3.2 g/dL. The trial does not include a vulnerable population. Participants are expected to use highly effective contraception methods if they are of childbearing potential. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **tagraxofusp** and **venetoclax** in patients with treatment-naive blastic plasmacytoid dendritic cell neoplasms (BPDCN). This is an open-label, phase II study, which will be conducted in a randomized, controlled manner. The trial aims to assess the primary endpoint of composite complete remission (cCR) after three cycles of the combination therapy. Secondary endpoints include objective response rate, safety profile, progression-free survival, and overall survival, among others.

The trial is expected to commence recruitment on January 31, 2025, and conclude by January 31, 2031. Participants will be involved in the study for a maximum treatment period of 72 weeks, with the possibility of early termination if specific conditions arise, such as adverse reactions or withdrawal of consent. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, renal and cardiac function, and a confirmed BPDCN diagnosis; follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes.

Inclusion criteria require participants to be over 18 years of age, with adequate renal and cardiac function, and the ability to provide informed consent. Exclusion criteria are not explicitly detailed in the provided data. The trial will utilize **venetoclax** in a film-coated tablet form for oral use, with a maximum daily dose of 400 mg, and **tagraxofusp** as a concentrate for solution for infusion, with a maximum daily dose of 12 µg/kg. The study is not categorized as low intervention and is classified as interventional, reflecting its phase II status and the investigational nature of the treatment combination.

The clinical trial involves the administration of **Venetoclax**, a BCL-2 inhibitor, which is provided in the form of a film-coated tablet. The active substance, **venetoclax**, is of chemical origin and is manufactured by AbbVie Deutschland GmbH & Co. KG. The maximum daily dose of venetoclax is 400 mg, administered orally. The treatment period for venetoclax is up to 24 weeks. Participants are required to adhere to the dosing schedule, and compliance is monitored throughout the study.

Additionally, the trial includes the use of **ELZONRIS**, a concentrate for solution for infusion, containing the active substance **tagraxofusp**. This substance is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and is produced by Stemline Therapeutics B.V. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 12 µg/kg, with a treatment period extending up to 72 hours. The administration of ELZONRIS is conducted in association with venetoclax, and participant compliance is closely monitored to ensure adherence to the treatment protocol.

The efficacy of the combination of **tagraxofusp** and **venetoclax** in the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be assessed primarily through the rate of composite complete remission (cCR). This is defined as complete remission (CR) or complete remission with incomplete marrow recovery (Cri), according to the European Leukemia Net 2022 definitions for acute myeloid leukemia (AML) and adapted for BPDCN. Additionally, a complete response with minimal residual skin abnormality (CRc[clinical]) is defined by a marked clearance of ≥ 75% of a patient’s skin lesions from baseline and a complete metabolic response after three cycles of the combination therapy.

The primary endpoint is the proportion of participants who achieve a cCR after three cycles of the combination therapy. Secondary endpoints include the objective response rate, which encompasses cCR and partial remission after three cycles, the safety profile of the combination, the proportion of patients with minimal residual disease (MRD) negative responses measured by flow cytometry, progression-free survival, duration of response, overall survival, and the proportion of patients bridged to allogeneic stem cell transplantation. Additionally, possible predictors of response with respect to cytogenetics and mutational status will be evaluated.