SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

August 11, 2015 07:00 ET

Threshold Pharmaceuticals and ATOMIC Initiate First Phase 2 Clinical Trial of Tarloxotinib Bromide* (TH-4000) in Patients With Advanced EGFR-Mutant, T790M-Negative Non-Small Cell Lung Cancer (NSCLC)

SOUTH SAN FRANCISCO, CA--(Marketwired - Aug 11, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: 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."

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.


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.

About Threshold Pharmaceuticals

Threshold Pharmaceuticals, Inc. is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in the microenvironments of most solid tumors as well as the bone marrows of some patients with hematologic malignancies. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (

Forward-Looking Statements

Except for statements of historical fact, the statements in this press release are forward-looking statements, including all statements regarding the potential therapeutic applications for tarloxotinib and its potential benefits, including as a potential treatment option in the NSCLC setting; and Threshold's planned Phase 2 clinical trial of tarloxotinib in patients with advanced head and neck cancer and the timing thereof. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to: the risks that Threshold's evaluation of tarloxotinib is at an early stage and it is possible that tarloxotinib may not be found to be safe or effective in the initiated and/or planned Phase 2 clinical trials of tarloxotinib or in any other studies of tarloxotinib that Threshold may conduct, and that Threshold may otherwise fail to realize the anticipated benefits of its licensing of this product candidate; the risk that preclinical studies and Phase 1 clinical trials of tarloxotinib may not predict the results of subsequent human clinical trials, including the risks that preclinical and Phase 1 clinical data that suggest that plasma concentrations of tarloxotinib that are active in EGFR-dependent tumor xenograft models in mice could be attained in patients with an acceptable therapeutic index may not accurately predict whether a safe and effective dose can be attained in the patient populations that Threshold is targeting; the difficulty and uncertainty of pharmaceutical product development, including the time and expense required to conduct clinical trials and analyze data, and the uncertainty of clinical success and regulatory approval; the ability of Threshold to enroll or complete ongoing and/or planned tarloxotinib clinical trials; Threshold's potential inability to develop a formulation of tarloxotinib with adequate quality that meets the specifications previously filed with the regulatory agency and that meets the need for testing in its clinical trials; issues arising in the regulatory process and the results of such clinical trials (including product safety issues and efficacy results); Threshold's dependence on single source suppliers for tarloxotinib, including the risk that these single source suppliers may be unable to meet clinical supply demands for tarloxotinib which could significantly delay the development of tarloxotinib; and Threshold's need for and the availability of resources to develop its product candidates and to support Threshold's operations. Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Quarterly Report on Form 10-Q, which has been filed with the Securities and Exchange Commission on July 30, 2015 and is available from the SEC's website ( and on our website ( under the heading "Investors". We undertake no duty to update any forward-looking statement made in this news release.

* Tarloxotinib bromide is the proposed International Nonproprietary Name (pINN)

Contact Information

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    Laura Hansen