P1, N=43, Recruiting, City of Hope Medical Center | Trial completion date: Jan 2027 --> Apr 2027 | Trial primary completion date: Jan 2027 --> Apr 2027

In conclusion, this large-scale, retrospective database analysis suggests that VEN + HMA is an effective therapeutic alternative to tagraxofusp in older patients for the management of BPDCN. Future studies are needed to prospectively validate these findings.

The new compound C4 shows  better ability to degrade eEF2K and stronger anti-cancer activity than C1. These findings not only uncover the pivotal role of the eEF2K/AURKA/SOX8 axis in TNBC progression, but also provide a promising lead compound for developing novel drug for treatment of TNBC.

P1/2, N=20, Recruiting, Stanford University | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2026 --> Oct 2027

P2, N=25, Terminated, Gruppo Italiano Malattie EMatologiche dell'Adulto | N=50 --> 25 | Recruiting --> Terminated; poor enrollment

Our study confirms that BPDCN is a very rare and difficult-to-treat disease. Underdiagnosis and underreporting in the literature pose further challenges. Symptoms at presentation seem to differ slightly between sexes and reaching a complete remission after first-line treatment remains crucial for a prolonged overall survival. Effective treatment protocols in first line include transplantation regimens (mainly allogenic, potentially also autologous) as well as ALL protocols. In order to understand the significance of tagraxofusp as a bridge to transplant or as a continuous monotherapy in elderly patients, further evaluation with longer follow-up periods is required. In general, analysis of the Swiss patients confirmed the results from the worldwide cohort.

BPDCN is frequently misidentified, but early, accurate diagnosis is critical to extending patient survival using tagraxofusp, a first-in-class CD123-targeted therapy, and increasing their chances of receiving a potentially curative stem cell transplantation. Cases of BPDCN in countries of the Gulf Cooperation Council are lower than the extrapolated incidence from other geographic locations due to lack of awareness of key diagnostic features, lack of consensus on the minimal phenotype for diagnosis, and lack of local immunohistochemistry testing facilities, contributing to underdiagnosis in this region. Practical recommendations, a streamlined diagnostic panel, and suggested multidisciplinary approaches based on expert experience regarding diagnostic and clinical challenges specific to this region, and a review of the literature are presented here to facilitate diagnosis of BPDCN in this region by primary care physicians, dermatologists, and hematologists.

P1/2, N=64, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

Our findings indicate that interfering with the inhibition of eEF2 results in elevated protein synthesis in HCT116 cells and is associated with the progression of malignancy in the colorectal cancer cell line, where eEF2K activity could provide a tumor suppressive role.

P1/2, N=82, Completed, Stemline Therapeutics, Inc. | Phase classification: P2 --> P1/2

P2, N=76, Recruiting, Stemline Therapeutics, Inc. | Not yet recruiting --> Recruiting

In conclusion, this study proposes that eEF2K alleviates DIC by inhibiting GSK3β and improving autophagy dysfunction. eEF2K is a promising therapeutic target against DIC.

P1, N=44, Recruiting, Karen Ballen, MD | Trial primary completion date: Jul 2024 --> Jul 2026

Now, with over 5 years since the first commercially approved targeted agent specifically dedicated for BPDCN, the CD123-targeted agent tagraxofusp, improvements have been demonstrated particularly in the frontline setting for patients with BPDCN. The field is abundant with hope, as it has experienced advancements including greater molecular characterization, expanded identification of potential targets for therapy beyond CD123, advent of combination therapies, improving parameters for stem cell transplantation, and novel clinical trials specifically available for patients with BPDCN.

P1/2, N=20, Not yet recruiting, Stanford University | Initiation date: Oct 2024 --> Jan 2025

The protein products of eEF2K are capable of localizing to the nucleus, cytoplasm, and cytosol, where they bind to a range of proteins, including ATP and calcium ions. These findings provide novel insights into the role of eEF2K in cancer biology and suggest that the targeting of eEF2K and eEF2 phosphorylation may offer promising therapeutic strategies.

Misdiagnosis or late diagnosis of this clinically heterogeneous BPDCN may lead to systemic spread and poor outcomes. Hence, prompt diagnosis and treatment are essential, with a multidisciplinary approach.

P1, N=43, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P2, N=76, Not yet recruiting, Stemline Therapeutics, Inc. | Initiation date: Aug 2024 --> Nov 2024

This case emphasizes the challenges of diagnosing and treating BPDCN, noting its rarity and absence of standard therapy. Tagraxofusp has shown promising results but presents safety concerns like capillary leak syndrome, particularly in elderly patients with comorbidities.

Currently, standard treatment strategies include clinical trials; chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and tagraxofusp-erzs (TAG, previously SL-401) which is the first-in-class targeted therapy against CD123...However, despite promising results, there are still patients who may be resistant to TAG monotherapy and/or who respond but eventually relapse. Herein, we discuss an important patient case of BPDCN treated with TAG and review BPDCN treatment strategies.

Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.

P1/2, N=20, Not yet recruiting, Stanford University

P2, N=3, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; The protocol was terminated early due to slow participant accrual and the sponsor not willing to provide the study drug.

P1/2, N=4, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=40 --> 4

P1, N=43, Not yet recruiting, City of Hope Medical Center

P2, N=76, Not yet recruiting, Stemline Therapeutics, Inc.

P1/2, N=46, Not yet recruiting, Darell Bigner

P1, N=72, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: May 2024 --> May 2025

P1, N=20, Not yet recruiting, University of Kansas Medical Center

In line with results from 13 published cases outside clinical trials in the literature, sustained responses were associated with CR after tagraxofusp treatment and subsequent alloHCT. Our results provide real-world evidence for safety and efficacy of tagraxofusp as first-line treatment for BPDCN.

P2, N=53, Recruiting, Joshua Zeidner | Not yet recruiting --> Recruiting

The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.

No abstract available

P1, N=0, Withdrawn, Jonsson Comprehensive Cancer Center | N=29 --> 0 | Not yet recruiting --> Withdrawn

In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

Targeted eEF2K blockade may result in cGAS-STING pathway activation, leading to enhanced infiltration and activity of NK cells within HCC tumors. The synergistic effect achieved by combining an eEF2K inhibitor with PD-1 antibody therapy represents a novel and promising approach for the treatment of HCC.

P1, N=36, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting | Phase classification: P1a/1b --> P1

P1, N=30, Recruiting, Annick Desjardins, MD | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=18, Active, not recruiting, Annick Desjardins, MD | Trial primary completion date: Dec 2023 --> Dec 2024