Date: 2016-09-29
Type of information: discontinuation of development
phase: 2
Announcement: discontinuation of development
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: recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS)
Therapeutic area: Cancer - Oncology
Country: Australia, USA
Trial
details: This phase 2 study is designed to evaluate the safety and activity of TH-4000, a hypoxia-activated prodrug in participants with recurrent or metastatic squamous cell carcinoma of the head and neck or skin. The study will enroll up to 68 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. Prior anti-EGFR antibody therapy is permitted. RECIST response rate is the primary endpoint. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. In addition to other target-specific biomarkers, hypoxia status will be measured at baseline using Threshold's proprietary PET imaging agent [18F]-HX4. The study is planned to be opened at 10 sites in the U.S. and Australia. (NCT02449681)
Latest
news: * On September 29, 2016, Threshold Pharmaceuticals announced interim data from its two Phase 2 proof-of-concept clinical trials of tarloxotinib. "While the response observed in our squamous cell carcinoma of the skin study with tarloxotinib was encouraging, the overall results from the two studies didn't meet the activity thresholds required to move forward the molecule forward despite the promising results seen in preclinical translational studies," said Barry Selick , Ph.D., Chief Executive Officer of Threshold. "As a result, we are making no further investment in this program". As a result, and taking into consideration the totality of the clinical data with tarloxotinib, enrollment in both Phase 2 clinical trials and further development of tarloxotinib will be discontinued. * On August 27, 2015, Threshold Pharmaceuticals announced that the company has initiated a Phase 2 clinical trial of tarloxotinib bromide, (TH-4000), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Elevated expression of wild-type EGFR and its stimulatory ligands occurs in the majority of squamous cell carcinomas. Aberrant EGFR signaling can lead to uncontrolled tumor cell growth. One mechanism likely to be involved is hypoxia, or low-oxygen conditions, which is a prevalent feature of solid tumors including squamous cell carcinomas. In preclinical studies hypoxia has been shown to increase EGFR signaling by upregulation, stabilization, and hyperphosphorylation of EGFR, through multiple mechanisms. Gene expression-based profiling of clinical samples supports the observations of a strong causal link between elevation in the tumor EGFR pathway and hypoxia signatures. Tarloxotinib bromide targets the activating mutations of EGFR (L858R and Del19) and wild-type, or "normal", EGFR. The Phase 2 clinical trial is a single-arm, open label study that will enroll up to 68 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. Prior anti-EGFR antibody therapy is permitted. RECIST response rate is the primary endpoint. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. In addition to other target-specific biomarkers, hypoxia status will be measured at baseline using Threshold's proprietary PET imaging agent [18F]-HX4. The study is planned to be opened at 10 sites in the U.S. and Australia .
In the first stage of the SCCS arm of the trial, a confirmed partial response was observed in 1 of 7 patients. According to the study design, the response rate was sufficient to expand the trial to evaluate additional patients.
However, of the 22 SCCHN patients who were assessed, although 8 achieved stable disease, none achieved a confirmed partial response.
