On August 11, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported 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, or "tarloxotinib" (TH-4000), 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 (Press release, Threshold Pharmaceuticals, AUG 11, 2015, View Source [SID:1234507197]). Schedule your 30 min Free 1stOncology Demo! Tarloxotinib is Threshold’s proprietary, hypoxia-activated, irreversible EGFR tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand.
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"While there has been recent progress in treating EGFR-mutant patients with acquired resistance to first-generation drugs driven through T790M mutations, an urgent need exists to develop treatments for patients whose disease has progressed due to other mechanisms of resistance," said D. Ross Camidge, M.D., Ph.D., Professor of Medicine/Oncology at the University of Colorado School of Medicine and Director of ATOMIC. "ATOMIC is committed to advancing the next generation of therapies for lung cancer, quickly, scientifically and efficiently. We are excited to collaborate with Threshold and begin this Phase 2 clinical trial of tarloxotinib, which has demonstrated, in preclinical studies, an ability to overcome resistance to conventional EGFR tyrosine kinase inhibitors at clinically relevant dose levels."
Aberrant EGFR signaling is implicated in the growth and spread of certain tumor types including NSCLC. The majority of patients with EGFR-mutant NSCLC who are treated with a currently available EGFR tyrosine kinase inhibitor, such as Tarceva (erlotinib), Gilotrif (afatinib) and Iressa (gefitinib), will develop resistance, due to a variety of mechanisms, to these targeted therapies in about a year.
"One largely unexplored mechanism of acquired resistance is through expression of not only mutant EGFR but also the normal ‘wild-type’ form of the receptor and its subsequent stimulation by growth factors produced in the tumor microenvironment," said Stephen V. Liu, M.D., Assistant Professor at Georgetown University and Principal Investigator of the Phase 2 clinical trial. "Unfortunately, the side effects of current EGFR tyrosine kinase inhibitors, including rash and diarrhea, prevent maximally efficacious inhibition of ‘wild-type’ EGFR in the tumor from being achieved. These side effects are mediated by non-targeted, systemic inhibition of ‘wild-type’ EGFR. In contrast, tarloxotinib is a prodrug designed to be preferentially activated in hypoxic, or low-oxygen, conditions commonly found in solid tumors including EGFR-mutant NSCLC, which may allow greater inhibition of EGFR signaling within the tumor while limiting the systemic side effects."
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.
"The initiation of this Phase 2 clinical trial marks a significant milestone for the development of tarloxotinib," said Tillman Pearce, M.D., Chief Medical Officer of Threshold. "Threshold now has the two most advanced hypoxia-activated prodrugs in clinical development, including evofosfamide, which is under investigation in two fully-enrolled, pivotal Phase 3 clinical trials. We are excited to collaborate with ATOMIC on evaluating tarloxotinib as a hypoxia-activated, molecularly-targeted prodrug in a selected population of patients with EGFR-mutant NSCLC. We plan to initiate a second Phase 2 trial of tarloxotinib in patients with advanced head and neck cancer this year."
About Tarloxotinib Bromide
Tarloxotinib bromide, or "tarloxotinib", (TH-4000; previously referred to as PR610 or Hypoxin) is a hypoxia-activated, covalent (irreversible) 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.
About NSCLC
NSCLC accounts for approximately 85 percent of the annual 1.8 million lung cancers diagnosed worldwide. EGFR activating mutations occur in approximately 15 percent of NSCLC cases in Caucasian patients and up to 35 percent in Asian patients. Tarceva, Gilotrif and Iressa, are the first and second-generation EGFR inhibitors currently approved for patients with the EGFR activating mutations. Nearly all patients ultimately progress on these therapies due to a variety of resistance mechanisms. Chemotherapy is a treatment option for many of these patients and tarloxotinib bromide represents a potential novel and targeted treatment option in this setting.