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]).

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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.

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.

On August 11, 2015 Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZ) (the "Company") reported that the independent Data and Safety Monitoring Board ("DSMB") for the pivotal Phase 3 ZoptEC (Zoptarelin Doxorubicin in Endometrial Cancer) study with zoptarelin doxorubicin in women with advanced, recurrent or metastatic endometrial cancer, will complete a pre-specified second interim efficacy and safety analysis of the compound in early October 2015 (Press release, AEterna Zentaris, AUG 11, 2015, View Source [SID:1234507196]).

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David Dodd, Chairman and CEO of Aeterna Zentaris, commented, "This past June 30, we announced that we had reached our goal of recruiting 500 patients for the Phase 3 ZoptEC study, marking the achievement of an important milestone in our efforts to commercialize this novel compound. Recently, we learned that the number of events required for the DSMB to conduct its second interim analysis had occurred. We are informed that the DSMB will conduct its review of the data in early October of this year, and we expect to be able to announce the results of the review soon thereafter. This review will be an important event in our development of zoptarelin doxorubicin. We are looking forward to learning the results of the DSMB’s analysis."

Commenting on the compound, Dr. Richard Sachse, the Company’s Chief Medical and Chief Scientific Officer, stated, "We believe that zoptarelin doxorubicin has the potential to become the first FDA approved medical therapy for advanced, recurrent endometrial cancer. This could result in its rapid adoption as a novel core therapy for treatment and management of advanced, recurrent endometrial cancer. Our hope is that the compound will improve and extend the quality of the lives of patients with this devastating disease."

About the ZoptEC Phase 3 trial

The ZoptEC Phase 3 trial is an open-label, randomized-controlled study, comparing the efficacy and safety of zoptarelin doxorubicin, a hybrid molecule composed of a synthetic peptide carrier and a well known chemotherapy agent, doxorubicin, to doxorubicin alone. The trial is fully recruited (over 500 patients) and is being conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration ("FDA"). Patients are centrally randomized in a 1:1 ratio and receive either zoptarelin doxorubicin (267 mg/m2) or doxorubicin (60 mg/m2) intravenously, every 3 weeks and for up to 9 cycles. Response will be evaluated every 3 cycles during treatment, thereafter, every 12 weeks until progression. All patients will be followed for survival as the primary efficacy endpoint ("EP"). Secondary EPs include progression free survival, objective response-rate, and clinical benefit rate.

For more information on this trial, please consult (ClinicalTrials.gov Identifier: NCT01767155; EudraCT No: 2012-005546-38; ZoptEC: Zoptarelin doxorubicin in endometrial cancer).

About Zoptarelin Doxorubicin

Zoptarelin doxorubicin represents a new targeting concept in oncology using a hybrid molecule composed of a synthetic peptide carrier and a well-known chemotherapy agent, doxorubicin. Zoptarelin doxorubicin is the first intravenous drug in advanced clinical development that directs the chemotherapy agent specifically to LHRH-receptor expressing tumors, which could result in a more targeted treatment with less damage to healthy tissue. The Company is currently conducting a ZoptEC (Zoptarelin doxorubicin in Endometrial Cancer) Phase 3 trial in women with advanced, recurrent or metastatic endometrial cancer, while zoptarelin doxorubicin is also tested in an investigator-initiated Phase 2 trial in prostate cancer. Aeterna Zentaris owns the worldwide rights to this compound except in China (including Hong Kong and Macau) where rights have been out-licensed to Sinopharm A-Think Pharmaceuticals, a subsidiary of Sinopharm, the largest medical and healthcare group in China and on Fortune’s Global 500 list. On April 16, 2015, the Company announced the filing of a patent application intended to strengthen the exclusivity of zoptarelin doxorubicin through a unique modification of the manufacturing process resulting in significantly lower cost.

About Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy in developed countries and develops when abnormal cells amass to form a tumor in the lining of the uterus. It largely affects women over the age of 50 with a higher prevalence in Caucasians and a higher mortality rate among African Americans. According to the American Cancer Society, there will be approximately 50,000 new cases of endometrial cancer in the U.S. alone in 2015, with about 20% of recurring disease.