Date: 2015-04-22
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the annual meeting of the American Association for Cancer Research (AACR)
Company: Threshold Pharmaceuticals (USA - CA)
Product: tarloxotinib (TH-4000)
Action
mechanism: kinase inhibitor/epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Tarloxotinib bromide (TH-4000; previously referred to as PR610 or Hypoxin™) is a hypoxia-activated, covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that targets the activating mutations of EGFR (L858R and Del19) and wild-type, or "normal", EGFR. Tarloxotinib is designed as a prodrug to selectively release its EGFR TKI upon encountering severe tumor hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant wild-type and mutant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the toxic side effects associated with currently available EGFR TKIs and systemic wild-type EGFR inhibition. Tarloxotinib is currently being evaluated in a Phase 2 proof-of-concept trial for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR TKI. A second Phase 2 proof-of-concept trial is planned to begin in 2015 for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.
Disease: non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On April 22, 2015, Threshold Pharmaceuticals announced preclinical data on TH-4000, its proprietary, molecularly-targeted, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) suggesting that TH-4000 may overcome resistance to therapy with conventional EGFR-TKIs. In a xenograft model of non-small cell lung cancer (NSCLC) in which both wild-type (normal) EGFR and mutant EGFR are present (a heterozygous model), TH-4000 was more active than the conventional EGFR-TKI erlotinib. Complete tumor control was observed in this model using human-equivalent doses of TH-4000 that were less than 15% of the maximum-tolerated dose defined previously in a Phase 1 clinical trial. The company believes the data support its planned Phase 2 clinical trials of TH-4000, including one in patients with EGFR-positive, T790M-negative NSCLC and the other in patients with recurrent/metastatic head and neck (H&N) cancer. The data were reported at the annual meeting of the American Association for Cancer Research (AACR) on Wednesday, April 22 , 8 AM - 12 PM EDT (Abstract #5358 in Poster Section #28) . Preclinical data reported at AACR demonstrated that TH-4000 is a pan-ErbB inhibitor, releasing a potent irreversible TKI of wild-type EGFR, mutant EGFR and HER2. In the PC9 xenograft model of NSCLC, which is heterozygous for wild-type and mutant (deletion 19) EGFR, a single dose of TH-4000 (equivalent to 20 mg/m2 in humans) showed prolonged prodrug residency and EGFR shutdown in tumor tissue for a week. In addition, while treatment with erlotinib alone resulted in only modest benefit, treatment with TH-4000, resulted in 9/9 complete responses, suggesting an ability to prevent or overcome resistance to TKI treatment. Furthermore, the PC9 model was determined to be only 8% hypoxic, suggesting that the complete responses observed with TH-4000 were due to the ability of TH-4000, once hypoxia-activated, to diffuse into the surrounding normoxic tumor tissue. Preclinical data presented also demonstrated that TH-4000 is highly active against WT EGFR-driven tumors, whereas approved EGFR-TKIs are substantially less active. It is believed the 'masked' design of TH-4000 allows WT EGFR signaling in tumor tissue to be targeted via hypoxia while sparing normal tissue signaling in the skin and GI tract, providing a potential therapeutic window. Data from a previous Phase 1 clinical trial of patients with advanced solid tumors were also reported at AACR. The maximum tolerated dose of TH-4000 administered as a 1-hour weekly intravenous infusion was established at 150 mg/m2. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue.
