SOUTH SAN FRANCISCO, CA, USA I August 27, 2015 I Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that the company has initiated a Phase 2 clinical trial of tarloxotinib bromide, or “tarloxotinib” (TH-4000), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Tarloxotinib is Threshold’s proprietary, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand.

“New and effective treatment options are urgently needed for patients with squamous cell carcinomas,” said Danny Rischin, M.D., Co-Director, Division of Cancer Medicine at Peter MacCallum Cancer Centre and Principal Investigator of the Phase 2 trial. “Tarloxotinib represents a novel treatment approach that may allow effective inhibition of EGFR signaling in the tumor microenvironment with relative sparing of normal tissues.”

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.1-6 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.7

“We are pleased that tarloxotinib is actively being investigated in two monotherapy Phase 2 proof-of-concept trials, the other being in patients with non-small cell lung cancer,” said Tillman Pearce, M.D., Chief Medical Officer of Threshold. “These clinical settings, in which EGFR is already a validated therapeutic target, represent opportune development paths for tarloxotinib, which is designed to exploit the reported overlap between elevated EGFR signaling and tumor hypoxia. By selectively targeting the hypoxic tumor microenvironment, tarloxotinib has the potential to increase the therapeutic index and overcome limitations of current EGFR inhibitor therapy, which may lead to improved outcomes for patients with these EGFR-dependent cancers.”

About the Phase 2 Clinical Trial

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.

About Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Most head and neck cancers, which include cancers of the larynx (voice box), throat, lips, mouth, nose, and salivary glands, begin in the squamous cells that line the moist surfaces inside the head and neck, and are therefore referred to as squamous cell carcinomas of the head and neck (SCCHN). SCCHN is diagnosed in approximately 59,000 people in the U.S. annually and is responsible for some 12,000 deaths.8 Historically, tobacco and alcohol use have been the greatest risk factors; more recently, infection with the human papilloma virus (HPV) has been recognized as a risk factor with a more favorable prognosis. For patients with advanced disease who have progressed on the standard regimen of platinum-based chemotherapy with or without cetuximab anti-EGFR therapy, further therapy with chemotherapy or cetuximab monotherapy is the standard of care, but response rates are about ten percent and disease progression occurs within two to three months.9

About Squamous Cell Carcinoma of the Skin (SCCS)

Non-melanoma skin cancers typically resulting from chronic sun exposure or other sources of ultraviolet rays are the most common types of cancer. Twenty percent of these skin cancers originate from squamous cells normally present in the outer layers of the skin (SCCS); five percent of SCCS will become locally advanced, recur, or metastasize. In the U.S., approximately 2,000 deaths per year are attributed to SCCS.10 As with SCCHN, SCCS is associated with EGFR overexpression and appear to be responsive to EGFR inhibitor therapy.11

About Tarloxotinib Bromide

Tarloxotinib bromide, or “tarloxotinib”, (TH-4000) 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. In addition to this second trial in squamous cell carcinomas, 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. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

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 (

SOURCE: Threshold Pharmaceuticals