Tarlox (tarloxotinib bromide) / Molecular Templates, Proacta, Signpath Pharma, Pathos - LARVOL DELTA

Development of hypoxia-activated prodrugs of AMPK inhibitors and evaluation in acute myeloid leukemia (AACR-NCI-EORTC 2025) - "Several HAPs have been developed, including Evofosfamide (TH-302) and Tarloxotinib (TH-4000), that utilize a nitroimidazole trigger that can be bioreduced under hypoxic conditions to release the active agent. In addition, we evaluated cellular target engagement in the MOLM-13 cell line by monitoring the phosphorylation of acetyl-CoA carboxylase (ACC) at Ser79 under both normal and hypoxic culture conditions. The development of HAPs of AMPK inhibitors have the potential to selectively sensitize drug resistant LSC to standard of care therapy or eliminate metabolically vulnerable LSCs as a single agent therapy."

Late-breaking abstract • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AMPK

Coenzyme Q10 as an Inhibitor of Effector Release from One-Electron-Reduced Bioreductive Anticancer Prodrugs. (PubMed, Molecules) - "Evidence is put forward suggesting that radical anions can undergo an electron transfer to ubiquinone (CoQ10, UQ) in competition with the fragmentation of the radical anions releasing effectors. The prior inhibition of the synthesis of UQ in cells is put forward as a possible approach to increase the effectiveness of such prodrugs in killing hypoxic tumor cells."

Journal • Oncology

Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals. (PubMed, Antiviral Res) - "We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (NB-DGJ), MON-DNJ, NAP-DNJ, NN-DGJ and NN-DNJ). Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2 breast cancer. (PubMed, Arch Toxicol) - "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."

Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • HER-2

Tarlox and Sotorasib in Patients With KRAS G12C Mutations (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: Medical University of South Carolina | Active, not recruiting ➔ Terminated; Study drug was discontinued by manufacturer for business reasons.

Trial termination • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Window of opportunity trial of Tarloxotinib combined with stereotactic body radiotherapy (SBRT) in advanced human papilloma virus (HPV) negative head & neck cancer. (ANZCTR) - P1 | N=12 | Terminated | Sponsor: Te Puriri O Te Ora Directorate of Cancer & Blood at Auckland City Hospital | Recruiting ➔ Terminated

Metastases • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Application and mechanism of tarloxotinib in HER2-positive breast cancer (ESMO 2023) - "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."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • ERBB3 • ERBB4 • HER-2 • PARP1

A Phase 1B Trial of Tarloxotinib and Sotorasib in Lung Cancer Patients with KRAS G12C Mutations (IASLC-WCLC 2023) - "Biomarker analysis is being performed to elucidate resistance mechanisms. The study opened in April 2022 and is currently enrolling."

Clinical • P1 data • Esophageal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS

Tarlox and Sotorasib in Patients With KRAS G12C Mutations (clinicaltrials.gov) - P1/2 | N=5 | Active, not recruiting | Sponsor: 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

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Study for Treatment of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Skin (clinicaltrials.gov) - P2 | N=30 | Terminated | Sponsor: Rain Therapeutics Inc. | N=60 ➔ 30

Enrollment change • Metastases • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Study for Treatment of Patients With EGFR Mutant, T790M-negative NSCLC (clinicaltrials.gov) - P2 | N=21 | Terminated | Sponsor: Rain Therapeutics Inc. | N=37 ➔ 21

Enrollment change • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Tarloxotinib is a hypoxia-activated pan-HER kinase inhibitor active against a broad range of HER-family oncogenes. (PubMed, Clin Cancer Res) - "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."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2 • NRG1

[VIRTUAL] First analysis of RAIN-701: Study of tarloxotinib in patients with non-small cell lung cancer (NSCLC) EGFR Exon 20 insertion, HER2-activating mutations & other solid tumours with NRG1/ERBB gene fusions (ESMO 2020) - P2 | "Funding: Rain Therapeutics. Clinical trial identification: NCT03805841."

Clinical • Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2 • NRG1

A phase II study of tarloxotinib (a hypoxia activated prodrug of a pan-erb tyrosine kinase inhibitor) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or skin. (PubMed, Invest New Drugs) - P2 | "Hypoxia-activated prodrugs represent a novel approach to cancer treatment, however, no clinically meaningful benefit for tarloxotinib in R/M HNSCC or CSCC was identified in this study."

Journal • P2 data • Head and Neck Cancer • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Squamous Cell Skin Cancer

Tarlox and Sotorasib in Patients With KRAS G12C Mutations (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Medical University of South Carolina

New P1/2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Window of opportunity trial of Tarloxotinib combined with stereotactic body radiotherapy (SBRT) in advanced human papilloma virus (HPV) negative head & neck cancer. (ANZCTR) - P1 | N=12 | Not yet recruiting | Sponsor: Te Puriri O Te Ora Directorate of Cancer & Blood at Auckland City Hospital

New P1 trial • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

"@StephenVLiu Why was Phase 2 trial of tarloxotinib in HER2m NSCLC terminated?" (@AnaPerez0809)

P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

RAIN: Study of Tarloxotinib in Pts With NSCLC (EGFR Exon 20 Insertion, HER2-activating Mutations) & Other Solid Tumors With NRG1/ERBB Gene Fusions (clinicaltrials.gov) - P2; N=41; Terminated; Sponsor: Rain Therapeutics Inc.; N=60 ➔ 41; Recruiting ➔ Terminated; enrollment pause

Clinical • EGFR exon 20 • Enrollment change • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2 • NRG1

Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study. (PubMed, Transl Lung Cancer Res) - "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."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • HER-2

Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19. (PubMed, Sci Rep) - "Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of M (IC 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PL (IC 300 nM, K 200 nM) and is the first reported PL inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • EGFR

NRG1 fusions: Biology to therapy. (PubMed, Lung Cancer) - "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."

Journal • Review • Lung Cancer • Oncology • Solid Tumor • NRG1

Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 13: NRG1 Fusions in Solid Tumors: The CRESTONE Trial (OncLive) - "Mark Socinski, MD: Before we close, I want to talk for a couple of minutes about NRG1 fusions. This is a fusion of the neuregulin 1 gene; these are rare tumors...Jyoti Patel, MD, FASCO: We have picked up a couple of these patients with this NRG1 fusion, and we have been enrolling-we have CRESTONE open as well as the Tarlox trials-trials testing tarloxotinib, which is an epoxy-activated EGFR TKI [tyrosine kinase inhibitor]....Benjamin Levy, MD: It does. It's an important alteration. It's extremely rare, but there may be some tip-offs, histologically, that may clue you in...Jonathan Trent, MD, PhD: What I can tell you is that it's very rare. I have not seen any patients at our center with this. If we are looking in the published literature...Lori Wirth, MD: Living in the Boston area, I am a big lobster aficionado and I am trying to figure out how that big fishing net can incorporate lobsters in it - how can I do this for my analogies?"

Biomarker • Video

Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy. (PubMed, Cells) - "Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness."

Journal • Review • Immune Modulation • Inflammation • Oncology • Solid Tumor

"So sorry, I misspelled tarloxotinib!!" (@benweinbergmd)

Activity of tarloxotinib-E in cells with EGFR exon-20 insertion mutations and mechanisms of acquired resistance. (PubMed, Thorac Cancer) - "These findings indicate that tarloxotinib-E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib-E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations."

EGFR Exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor