ALRN-6924

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Jul 2023 --> Apr 2025

P1, N=21, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | N=69 --> 21

While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

A recent report describes that ALRN-6924, an ATSP-7041 analog, inhibited OATP activities in vivo; therefore, we focused on the interaction between ATSP-7041 and OATP1B1 to demonstrate that ATSP-7041, as a higher molecular weight stapled peptide, is a substrate and strong inhibitor of OATP1B1 activity. Our findings demonstrated the possibility of transporter-mediated DDI potential by high molecular weight stapled peptides and the necessity of their evaluation for drug development.

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2023 --> Sep 2023 | Trial primary completion date: Jun 2023 --> Sep 2023

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration.

P1b, N=6, Terminated, Aileron Therapeutics, Inc. | N=26 --> 6 | Trial completion date: Jan 2024 --> Feb 2023 | Recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Feb 2023; The study has been terminated early given that the first four patients enrolled have experienced Grade 4 neutropenia and alopecia after cycle 1 and as such failed to meet the primary endpoint and the main secondary endpoint.

P1b, N=26, Recruiting, Aileron Therapeutics, Inc.

P1b, N=35, Terminated, Aileron Therapeutics, Inc. | Active, not recruiting --> Terminated; With a favorable safety profile the difference between treatment groups for the primary composite endpoint was not sufficient to generate statistically significant results with the targeted sample size

To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.

P1b, N=35, Active, not recruiting, Aileron Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=60 --> 35

P1, N=69, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of DNMT3A primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing DNMT3A R882X mutations.

No abstract available

ALRN-6924 was well tolerated and demonstrated anti-tumor activity.

Furthermore, MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in melanoma patients. Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy.

P1b, N=60, Recruiting, Aileron Therapeutics, Inc. | Active, not recruiting --> Recruiting | Phase classification: P1b/2 --> P1b

P1b/2, N=60, Active, not recruiting, Aileron Therapeutics | Recruiting --> Active, not recruiting | N=120 --> 60 | Trial completion date: May 2021 --> Nov 2022 | Trial primary completion date: Mar 2021 --> Jun 2022

Drug screening of tumor cells support the efficacy of novel targeted agents and indicate that these tumors are resistant to frontline standard chemotherapy, cisplatin and doxorubicin. These novel orthotopic PDX models of HB fully recapitulate the primary tumors and represent a platform for clinically relevant drug screening and testing. Further studies of the sub-clones of disease that grow in the animals will yield information about particularly aggressive HBs.

The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Several promising drugs are in the horizon, including the hypoxia-inducible factor stabilizer roxadustat, telomerase inhibitor imetelstat, oral hypomethylating agents (CC-486), TP53 modulators (APR-246 and ALRN-6924), and the anti-CD47 antibody magrolimab. Targeted therapies approved for acute myeloid leukemia treatment, such as isocitrate dehdyrogenase inhibitors and venetoclax, are also being studied for use in MDS. In this review, we provide a brief overview of pathogenesis and current treatment strategies in MDS followed by a discussion of newer agents that are under clinical investigation.

P1/2, N=149, Completed, Aileron Therapeutics | Active, not recruiting --> Completed

P1, N=69, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2020 --> Jun 2022

P1/2, N=149, Active, not recruiting, Aileron Therapeutics | Recruiting --> Active, not recruiting