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: patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR tyrosine kinase inhibitor and are progressing on treatment, but have not acquired the T790M resistance mutation
Therapeutic area: Cancer - Oncology
Country: Australia, USA
Trial
details: The Phase 2 clinical trial is a single-arm, open label study that will enroll up to 37 patients with Stage IV NSCLC who have a sensitizing EGFR mutation and who have progressed on EGFR tyrosine kinase inhibitor therapy (with no intervening therapy), and who subsequently test negative for the T790M mutation on post-progression biopsy. Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. 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 will be open at 12 sites in the U.S. and Australia.
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 11, 2015, Threshold Pharmaceuticals announced that the company, in collaboration with the Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC), has initiated the first Phase 2 clinical trial of tarloxotinib bromide for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR tyrosine kinase inhibitor and are progressing on treatment, but have not acquired the T790M resistance mutation. The Phase 2 clinical trial is a single-arm, open label study that will enroll up to 37 patients with Stage IV NSCLC who have a sensitizing EGFR mutation and who have progressed on EGFR tyrosine kinase inhibitor therapy (with no intervening therapy), and who subsequently test negative for the T790M mutation on post-progression biopsy. Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. 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 will be open at 12 sites in the U.S. and Australia. Threshold also plans to initiate a second Phase 2 trial of tarloxotinib in patients with advanced head and neck cancer this year.
Tarloxotinib in patients with EGFR-mutant, T790M-negative, advanced non-small cell lung cancer (NSCLC) (TH-CR-601): In the first stage of the trial, a response rate greater than or equal to 4 out of 19 patients was the threshold for expansion and continuation of the trial. Per protocol response is defined as tumor shrinkage (a partial or complete response). Although 7 of 21 assessed patients achieved stable disease, no patients achieved a confirmed partial response.
