P1, N=119, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P3, N=263, Not yet recruiting, Boehringer Ingelheim

P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Mar 2023 --> Dec 2023

P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Dec 2023 --> Mar 2023

P1, N=140, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1

Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

P3, N=240, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P2, N=155, Recruiting, Boehringer Ingelheim | Phase classification: P2a/2b --> P2

P1, N=269, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1 | N=204 --> 269

P1, N=16, Recruiting, Boehringer Ingelheim | Trial primary completion date: Feb 2024 --> May 2024

"Burning Rock Biotech Limited...is pleased to announce that the Company and Boehringer Ingelheim officially have signed the Master Service Agreement (MSA) in the field of oncology companion diagnostics. This agreement aims to provide Chinese patients with safer, more efficient, and precise treatment options and diagnostic methods, thereby promoting innovation and development in cancer treatment. This partnership will primarily focus on advancing the clinical trials related to Boehringer Ingelheim's MDM2-p53 antagonist, brigimadlin (BI 907828), and the development of companion diagnostic products in China."

P2, N=120, Not yet recruiting, Institut Bergonié

These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

P3, N=240, Not yet recruiting, Boehringer Ingelheim

P2/3, N=386, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=32, Recruiting, Boehringer Ingelheim | N=16 --> 32 | Trial primary completion date: Aug 2023 --> Aug 2024

This mutation analysis represents one of the most robust assessments of longitudinal ctDNA by NGS for TP53 from an MDM2–p53 antagonist trial in liposarcoma. While acquired mutations in TP53 are very common, these data suggest that brigimadlin does not systematically lead to broad acquisition of resistance by inducing alterations in TP53.

As evidence of target engagement, time- and dose-dependent increases in GDF-15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in well-differentiated or dedifferentiated liposarcoma patients (100% and 75% disease control rates, respectively).

Conclusions BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including those with BTC; dose expansion is ongoing. BI 907828 is being further assessed in pts with BTC in the phase IIa/IIb open-label Brightline-2 trial (NCT05512377).

BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.

Currently, ten patients with BTC had received BI 907828 ± ezabenlimab (an immune checkpoint inhibitor). The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks, or until study discontinuation. As of February 2023, 16 patients have been enrolled.Clinical trial identification: NCT05512377.Editorial acknowledgement: Medical writing assistance, funded by Boehringer Ingelheim, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, during the preparation of this abstract.Legal entity responsible for the study: Boehringer Ingelheim.

This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381.

E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies.

"Foundation Medicine, Inc...announced a global collaboration with Boehringer Ingelheim to develop the company’s tissue-based comprehensive genomic profiling test, FoundationOne^®CDx, as a companion diagnostic for Boehringer Ingelheim’s investigational MDM2-p53 antagonist, BI 907828, in the United States, Japan and European Union."

P2a/2b, N=130, Recruiting, Boehringer Ingelheim | N=100 --> 130

BI-907828 provides a promising new therapeutic option for patients with TP53 wild-type primary brain tumors.

P2a/2b, N=100, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=46, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, an MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type cancers. In Phase Ia (dose escalation), patients with advanced/metastatic solid tumors received escalating doses of BI 907828 guided by a Bayesian Logistic Regression Model (starting dose 10 mg orally) plus ezabenlimab 240 mg (anti-PD-1 antibody) and BI 754111 600 mg (anti-LAG-3 antibody) every 21 days (q3w). The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven patients remain on treatment; recruitment is ongoing.

We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.

The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

In HCT116 cell xenograft nude mouse model, administration of shp52-ZER6 combined with an MDM2-p53 binding inhibitor nutlin-3 exerted synergistic antitumor response. In conclusion, this study reveals that p52-ZER6 might be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.

In addition, the combination treatment revealed significant up-regulation of several cancer suppressor proteins in the whole lysate, cytoplasm, and nucleus. Finally, our results confirm that the combination of Selinexor with RG-7388 can induce a caspase-mediated apoptotic mechanism via up-regulation of p53 and p21.

Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.

P1, N=35, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=24, Recruiting, Centre Leon Berard | Trial primary completion date: Feb 2022 --> Sep 2022

Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.

P1/2, N=32, Not yet recruiting, Novartis Pharmaceuticals

P1, N=16, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

In addition, this combination treatment led to enhanced expression of apoptosis and autophagy-related genes in ALL cell lines. The results declared that AMG232 as an MDM-2 inhibitor could be an effective approach to enhance antitumor effects of Doxorubicin on NALM-6 cells as well as an effective future treatment for ALL patients.

We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53-RTK NSCLC via a genome-wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.