Threshold Pharma, ATOMIC Initiate First Phase 2 Trial of TH-4000 in Patients with Advanced EGFR-Mutant, T790M-NSCLC

Threshold Pharmaceuticals, Inc. THLD today 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, 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. Tarloxotinib is Threshold's proprietary, hypoxia-activated, irreversible EGFR tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand. "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."