A Phase 1b Dose Escalation Study of the Safety and Pharmacodynamics of Brontictuzumab in Combination With Chemotherapy for Subjects With Previously Treated Metastatic Colorectal Cancer

A Phase 1b Dose Escalation Study of the Safety and Pharmacodynamics of Brontictuzumab in Combination with Chemotherapy for Subjects with Previously Treated Metastatic Colorectal Cancer.

Start Date01 Jan 2017

Sponsor / Collaborator-

NCT02662608

/ CompletedNot ApplicableIIT

NOTCH 1 Inhibitor Brontictuzumab for Adenoid Cystic Carcinoma Bearing Two Activating NOTCH1 Mutations

The goal of this study is to start treatment with the NOTCH1 inhibitor brontictuzumab in an attempt to control tumors and prolong survival. The therapy involves participant being given the drug brontictuzumab to treat adenoid cystic carcinoma (ACC) with NOTCH 1 mutations. This is considered an investigational treatment.

Start Date29 Dec 2015

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

NCT01778439

/ CompletedPhase 1

A Phase 1 Dose Escalation Study of OMP-52M51 in Subjects With Solid Tumors

This is an open-label Phase 1a dose escalation study of single-agent OMP-52M51 in subjects with relapsed or refractory solid tumors. Study includes a dose escalation phase and expansion phase. Subjects will be assessed for safety, immunogenicity, pharmacokinetics, biomarkers, and efficacy.

Start Date01 Feb 2013

Sponsor / Collaborator-

100 Clinical Results associated with Brontictuzumab

100 Translational Medicine associated with Brontictuzumab

100 Patents (Medical) associated with Brontictuzumab

Literatures (Medical) associated with Brontictuzumab

01 Mar 2025·Cancer Medicine

Clinical Outcomes With Notch Inhibitors in Notch‐Activated Recurrent/Metastatic Adenoid Cystic Carcinoma

Article

Author: Yoshitsugu Mitani ; Adel K. El-Naggar ; Juliana M. Siqueira ; Luana G. de Sousa ; Kaiwen Wang ; Eduardo Dal Lago ; Renata Ferrarotto ; Camilla O. Hoff ; Flavia Bonini

ABSTRACT:

Background:

Adenoid cystic carcinoma (ACC) with NOTCH‐activating mutations presents a clinical challenge due to its poor prognosis. NOTCH inhibitors have emerged as a potential therapy for ACC patients with NOTCH activation. This study aimed to evaluate the efficacy of NOTCH inhibitors in this patient population.

Methods:

A retrospective analysis was conducted on patients with metastatic ACC harboring NOTCH pathway activation, who received NOTCH inhibitors at MD Anderson Cancer Center. NOTCH inhibitors included AL101, a gamma‐secretase inhibitor, and brontictuzumab, an antibody targeting NOTCH1. NOTCH pathway activation was assessed through genomic analysis for NOTCH‐activating mutations or immunohistochemistry for NOTCH1 intracellular domain (NICD1). Efficacy endpoints included best overall response (BOR) and progression‐free survival (PFS) per RECIST or MD Anderson bone response criteria.

Results:

Twenty‐nine patients were included, with a predominance of solid histology (86%). NOTCH‐activating mutations were identified in 82% of patients, and 95% showed positive NICD1 staining. BOR revealed partial response in 17% of patients, stable disease in 55%, and progressive disease in 28%. Median response duration was longer for AL101 compared to brontictuzumab (9.9 vs. 1.7 months, p = 0.04). Median PFS with NOTCH inhibitor was 4.2 months (95% CI 2.7–8.6 months). Progression of nontarget lesions occurred in 34% of patients. Comparison with prior therapy showed longer PFS with NOTCH inhibitors (HR 0.38, 95% CI 0.19–0.78, p = 0.0065).

Conclusion:

NOTCH inhibitors demonstrate activity in NOTCH‐activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity.

01 Mar 2024·Toxicology and applied pharmacology

Anti-NOTCH1 therapy with OMP-52 M51 inhibits salivary adenoid cystic carcinoma by depressing epithelial-mesenchymal transition (EMT) process and inducing ferroptosis

Article

Author: Hu, Zelong ; Sun, Minglei ; Qiao, Quanxin ; Li, Ran ; Zhou, Die

Salivary adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, and the mechanisms underlying its progression still remain poorly understood without efficient therapies. NOTCH1, an evolutionally conserved cell-cell signaling pathway, is involved in the progression of ACC. In our study, we attempted to explore whether NOTCH1 suppression using the monoclonal anti-NOTCH1 antibody OMP-52 M51 could be of potential for ACC treatment. Here, we identified NOTCH1 elevation in human ACC tissues compared with the matched normal samples. Patients with metastasis expressed much higher NOTCH1. We then found that OMP-52 M51 markedly reduced the expression of NOTCH1 and its intracellular active form NICD1 (NOTCH1 intracellular domain). Importantly, OMP-52 M51 markedly reduced the proliferation, migration and invasion of ACC cells. RNA-Seq and in vitro studies further showed that OMP-52 M51 significantly induced ferroptosis in ACC cells, indicated by the increased cellular malondialdehyde (MDA), iron contents and lipid ROS production, and decreased glutathione (GSH) levels. Further, remarkable glutathione peroxidase 4 (GPX4) reduction was detected in ACC cells with OMP-52 M51 treatment. However, promoting NOTCH1 expression markedly abolished the function of OMP-52 M51 to induce ferroptosis. Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC.

01 May 2020·HaematologicaQ1 · MEDICINE

Dissecting molecular mechanisms of resistance to NOTCH1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts

Q1 · MEDICINE

Article

Author: Minuzzo, Sonia ; Frasson, Chiara ; Indraccolo, Stefano ; Pinazza, Marica ; Pezzè, Laura ; Palumbo, Pietro ; Agnusdei, Valentina ; Pfeffer, Ulrich ; Ciribilli, Yari ; Amadori, Alberto ; Pasqualini, Lorenza ; Carella, Massimo ; Bianco, Paola Del ; Tognon, Martina ; Gasparini, Alessandra ; Amaro, Adriana Agnese

Despite substantial progress in treatment of T-cell acute lymphoblastic leukemia (T-ALL), mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further improvements in survival demand better understanding of T-ALL biology and development of new therapeutic strategies. The Notch pathway has been involved in the pathogenesis of this disease and various therapeutic strategies are currently under development, including selective targeting of NOTCH receptors by inhibitory antibodies. We previously demonstrated that the NOTCH1-specific neutralizing antibody OMP52M51 prolongs survival in TALL patient-derived xenografts bearing NOTCH1/FBW7 mutations. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenomenon. Multi-level molecular characterization of T-ALL cells resistant to NOTCH1 blockade and serial transplantation experiments uncovered heterogeneous types of resistance, not previously reported with other Notch inhibitors. In one model, resistance appeared after 156 days of treatment, it was stable and associated with loss of Notch inhibition, reduced mutational load and acquired NOTCH1 mutations potentially affecting the stability of the heterodimerization domain. Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-regulation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of NOTCH1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade NOTCH1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors.

News (Medical) associated with Brontictuzumab

17 Apr 2017

·www.biospace.com

When It Rains, It Pours: Bay Area’s OncoMed Tanks Again as Lung Cancer Med Fails Phase II, Discontinues Phase I Study

April 17, 2017 By Alex Keown , BioSpace.com Breaking News Staff REDWOOD CITY, Calif. – Shares of OncoMed Pharmaceuticals are down more than 18 percent this morning after the company announced its mid-stage combination lung cancer treatment failed to meet endpoints. OncoMed said tarextumab (anti-Notch2/3, OMP-59R5) in combination with etoposide and a chemotherapy drug to treat patients with extensive-stage small cell lung cancer showed results that were “undifferentiated from those of chemotherapy plus placebo.” As a result, the company said the trial did not meet primary endpoints of progression-free survival, nor secondary endpoints of overall survival. The median progression-free survival for tarextumab plus chemotherapy was 5.6 months versus 5.5 months for chemotherapy plus placebo. Overall response rates were 68.5 percent and 70.8 percent in the tarextumab and placebo arms respectively, the company said. Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. The drug is part of OncoMed’s collaboration with GlaxoSmithKline . Small cell lung cancer is expected to make up between 10 and 15 percent of the 224,390 newly diagnosed lung cancer cases and the 158,080 deaths estimated to occur in the U.S. Current standard of care in treating small cell lung cancer is the chemotherapeutic etoposide in combination with either cisplatin or carboplatin. “Small cell lung cancer is a very difficult-to-treat disease and unfortunately, tarextumab did not show benefit over placebo in this Phase 2 trial,” Paul Hastings , OncoMed’s chairman and chief executive officer said in a statement. Additionally, OncoMed said it will discontinue enrollment in the Phase 1b clinical trial of brontictuzumab (anti-Notch1, OMP-52M51) in combination with trifluridine/tipiracil (Lonsur) in third-line colorectal cancer patients. The combination of brontictuzumab plus chemotherapy was not tolerable in this patient population. April has not been kind to OncoMed. On April 10, the company announced its partnership with Bayer to develop two drugs, vantictumab and ipafricept , both Wnt pathway inhibitors, had ended due to “strategic reasons.” With Bayer’s withdrawal, OncoMed retains worldwide rights to both drugs. Also on April 10, the company announced it was terminating a Phase II trial testing demcizumab in combination with Abraxane as a first-line treatment in metastic pancreatic cancer after the drug failed to meet endpoints. Due to the events announced today and last week, Hastings said the company will undergo an immediate comprehensive portfolio prioritization review. “The immediate task ahead is to thoroughly examine the available data, our resources and the opportunities to re-focus our efforts. We ended the first quarter of 2017 with $156.9 million in cash and short-term investments,” Hastings said.

Phase 2Clinical ResultPhase 1Phase 3Clinical Trial Failure

100 Deals associated with Brontictuzumab

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KEGG	Wiki	ATC	Drug Bank
D11229	Brontictuzumab	-	DB12737

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Colorectal Carcinoma	Phase 1	United States	-	01 Jan 2017
Malignant Solid Neoplasm	Phase 1	United States	-	01 Feb 2013
Relapsed Solid Neoplasm	Phase 1	United States	-	01 Feb 2013
Lymphoma	Phase 1	United States	-	01 Oct 2012

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01778439 (Pubmed \| Ann Oncol) Manual	Phase 1	Solid tumor	48	brontictuzumab (33 in dose escalation and 15 in the expansion phase)	wdwjjeywxv(yvdenxktgi) = diarrhea (71%), fatigue (44%), nausea (40%), vomiting (21%), and AST increase (21%) nssswqerhy (zuxqniilcz )	Positive	01 Jul 2018
NCT02662608 (CTgov)	Not Applicable	Adenoid Cystic Carcinoma	1	Brontictuzumab	nadrcsbacp = iwwrsjtkpo jiifuiorwf (gfycqtvbns, pkwleyppzt - cpijzbddys) View more	-	16 May 2017

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