Tarlox (tarloxotinib bromide)

P1/2, N=5, Terminated, Medical University of South Carolina | Active, not recruiting --> Terminated; Study drug was discontinued by manufacturer for business reasons.

We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2 breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2 breast cancer.

P1, N=12, Terminated, Te Puriri O Te Ora Directorate of Cancer & Blood at Auckland City Hospital | Recruiting --> Terminated

Methods HER2-positive breast cancer BT-474, SK-BR-3, HCC-1954 and JIMT-1 cells were treated with different concentrations of Tarloxotinib-E, Lapatinib and Tucatinib. Conclusions Tarloxotinib released Tarloxotinib-E under hypoxic microenvironment of breast tumors, and inhibited the phosphorylation of HER2 dimers and downstream pathways to induce apoptosis in HER2-positive cells through a ROS-dependent manner. This lays a foundation for the further development of Tarloxotinib in HER2-positive breast cancer.

Biomarker analysis is being performed to elucidate resistance mechanisms. The study opened in April 2022 and is currently enrolling.

P1/2, N=5, Active, not recruiting, Medical University of South Carolina | Recruiting --> Active, not recruiting | N=30 --> 5 | Trial completion date: Dec 2024 --> Dec 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

P2, N=21, Terminated, Rain Therapeutics Inc. | N=37 --> 21

P1/2, N=30, Recruiting, Medical University of South Carolina

P2, N=41, Terminated, Rain Therapeutics Inc. | N=60 --> 41 | Recruiting --> Terminated; enrollment pause

Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.

Supporting data are limited to case reports and small series for now, but prospective trials are underway. While our understanding of these fusions is still evolving, it is clear that NRG1 will be a clinically relevant finding in the years to come.

Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor vs. normal tissue and this activity can translate into clinical activity in patients.

Funding: Rain Therapeutics. Clinical trial identification: NCT03805841.

Tumor responses have been observed with tyrosine kinase inhibitors afatinib and tarloxotinib, but durable responses are rare and emergence of toxicity and resistance to these drugs could not be avoided...In vivo activity of 9F7-F11 was evaluated in comparison to MM121 using xenograft models with MDA-MB-175 breast cancer cell line or CTG-0943 patient-derived pancreatic tumor bearing respectively DOC4-NRG1 and APP-NRG1 fusion... 9F7-F11 antibody displays a unique potential for targeted treatment of NRG1-positive cancers. 9F7-F11 binding to HER3 is promoted by the ligand NRG1. This binding property was translated in vivo by an outstanding activity against xenograft models bearing NRG1 fusion, characterized by 100% of eradicated tumors.