(Filing, 10-Q, Idera Pharmaceuticals, NOV 6, 2015, View Source [SID:1234508067])

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On November 6, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported new preclinical data demonstrating that tarloxotinib bromide*, or tarloxotinib, may overcome resistance to first- and second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (Press release, Threshold Pharmaceuticals, NOV 6, 2015, View Source [SID:1234508073]). The data will be reported today in two scientific posters (Abstracts A66 and A67) at the AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting being held November 5-9, 2015, Boston. Tarloxotinib is Threshold’s proprietary hypoxia-activated prodrug of an irreversible EGFR TKI exclusively licensed from the University of Auckland, New Zealand.

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The research to be reported at the meeting focuses on preclinical models of EGFR-dependent cancers including non-small cell lung cancer (NSCLC) and squamous cell carcinomas of the head and neck (SCCHN) or skin (SCCS). These types of cancers are currently treated with drugs that block the activity of EGFR to interfere with tumor cell growth, but most tumors ultimately become resistant to therapy, and some do not respond at all.

Scientists are trying to understand the mechanisms underlying EGFR inhibitor resistance and discover new treatment options for patients with EGFR-driven cancers.

At the meeting, Adam Patterson, Ph.D. and Jeff Smaill, Ph.D., of the University of Auckland, New Zealand, will report that switching to low-dose tarloxotinib treatment in laboratory models of NSCLC resulted in significant regression of tumors that were progressing despite ongoing treatment with erlotinib, a first-generation EGFR TKI. These tumor models were heterozygous for EGFR whereby both wild-type (normal) and mutant (abnormal) forms of EGFR were present.

Independent research has shown that persistent wild-type EGFR signaling is associated with TKI resistance1, and patients with heterozygous EGFR-mutant NSCLC have worse outcomes following EGFR TKI therapy than those with pure mutant-EGFR disease2.

"Our research supports the hypothesis that persistent wild-type EGFR signaling within the tumor may be an important yet underappreciated mechanism of resistance to TKIs," Patterson said.

To test for the role of wild-type EGFR signaling in TKI resistance, Patterson and colleagues engineered one NSCLC model to have extra copies of the gene for wild-type EGFR. In the original parental heterozygous model, treatment with osimertinib (AZD9291), a third-generation TKI designed to "spare" wild-type EGFR, led to tumor regressions. In contrast, in the genetically engineered model with about 40% more wild-type EGFR, tumors started to regrow after initially responding to osimertinib. Tumor regrowth was brought under control upon switching to tarloxotinib treatment, which resulted in immediate and marked tumor regressions.

"Our preliminary findings suggest that tarloxotinib may be able to overcome wild-type EGFR-driven resistance to TKI therapy," Patterson said. "We believe this is related to the role of hypoxia in driving wild-type EGFR signaling within tumors coupled with the hypoxia-activation of tarloxotinib."

Using special imaging techniques, the team led by Patterson and Smaill were able to show a spatial overlap between hypoxic regions within tumors and EGFR signaling. Similarly, they were able to visualize the areas within a tumor where tarloxotinib released its TKI and found these areas to comprise the hypoxic compartment.

"Through collaboration with Dr. Angus Grey from the University of Auckland, we have for the first time demonstrated the mechanism of action of a hypoxia-activated prodrug in a human tumor model using MALDI Imaging Mass Spectrometry. This promises to be a very important technique for this field moving forward," Patterson said.

The scientists also presented data on tarloxotinib in models of SCCHN and SCCS. Across multiple cancer in vitro cell lines, tarloxotinib’s TKI exhibited greater anti-proliferative activity and consistently silenced EGFR signaling to a greater extent than equimolar concentrations of cetuximab, afatinib or dacomitinib. When tested in in vivo models, tarloxotinib was more effective compared to afatinib in controlling SCCS tumor growth, and compared to cetuximab in controlling SCCHN tumor growth. A single dose of tarloxotinib significantly reduced the hypoxic compartment in a SCCHN tumor model.

"Taken all together, the data suggest that preferential activation of tarloxotinib in the hypoxic tumor microenvironment leads to reduction of the hypoxic compartment and effective silencing of EGFR signaling within the tumor," Smaill said. "Tumor-targeted activation of tarloxotinib may limit systemic side effects, and wild-type EGFR shut down may address an apparently important mechanism of TKI resistance, both potentially contributing to better outcomes for patients with EGFR-dependent cancers."

"This important translational work continues to support our ongoing proof-of-concept Phase 2 trials in patients with NSCLC and in patients with SCCHN and SCCS," said Tillman Pearce, MD, Chief Medical Officer at Threshold. "Initial PET imaging using our proprietary hypoxia imaging agent, [18F]-HX4, shows that imaging hypoxia in these tumors is possible. We hope that by combining imaging with response data we can start to determine which patients would benefit most from tarloxotinib therapy. We look forward to having preliminary results from these studies in the first half of 2016."

About Non-Small Cell Lung Cancer

Lung cancer is the most common cause of death from cancer worldwide; an estimated 1.8 million new cases were diagnosed in 20123. The most common type of lung cancer, non-small cell lung cancer (NSCLC), accounts for approximately 85 to 90 percent of cases4. EGFR activating mutations occur in approximately 10 percent of NSCLC cases in Caucasian patients and up to 35 percent in Asian patients5. Tarceva, Iressa, and Gilotrif 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.

About Squamous Cell Carcinomas Head and Neck

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 deaths6. In the recurrent/metastatic setting, chemotherapy or cetuximab monotherapy is the standard of care with response rates are about ten percent and disease progression occurs within two to three months.7

About Squamous Cell Carcinomas of the Skin

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 SCCS8. As with SCCHN, SCCS is associated with EGFR overexpression and appear to be responsive to EGFR inhibitor therapy9.

About Tarloxotinib Bromide

Tarloxotinib bromide, or "tarloxotinib," is a prodrug designed to selectively release a covalent (irreversible) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the systemic side effects associated with currently available EGFR tyrosine kinase inhibitors. Tarloxotinib is currently being evaluated in two Phase 2 proof-of-concept trials: one for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR tyrosine kinase inhibitor, and the other for patients with recurrent or metastatic squamous cell carcinomas 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 [18F]-HX4

[18F]-HX4 [flortanidazole (18F)] is a novel investigational tumor hypoxia tracer developed to potentially identify and quantify the degree of hypoxia in tumors in vivo. Positron emission tomography (PET) is a nuclear medical imaging technique that non-invasively produces a three-dimensional image of functional processes in the entire body. PET is routinely used to inform physicians on diagnosis and treatment of cancer and is used in cancer treatment centers globally. [18F]HX4 has a 2-nitroimidazole "trigger" that is designed to be activated under the extreme hypoxic conditions generally found in tumors but not typically in normal healthy tissue. Clinical data has demonstrated the potential of [18F]HX4 to quantify the degree of hypoxia within different tumors.

On November 6, 2015 Cancer Research UK reported that it, The Lustgarten Foundation (link is external), and Stand Up To Cancer have come together in an international collaboration worth £8 million ($12 million) to announce funding for a pancreatic cancer research ‘Dream Team’ (Press release, Cancer Research UK, NOV 6, 2015, View Source [SID:1234508074]).

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"These are among the finest researchers in the world and we’re really excited by the potential of their ideas in the fight against this terrible disease" – Dr Iain Foulkes, Cancer Research UK

This innovative funding approach, into a cancer with low survival rates and in urgent need of better treatments, will support over 24 researchers across the UK and US over the next three years.

This transatlantic ‘Dream Team’ of top researchers will tackle the toughest questions in pancreatic cancer. The initiative will research new ways to turn off faulty molecular switches in pancreatic cancer cells, which control the behaviour of a wide range of genes that can play a part in the development of the disease.

Ultimately the research aims to increase the effectiveness of chemotherapy and harness the power of the patient’s own immune system, leading to new ways to prevent pancreatic cancer from returning after initial treatment.

Professor Gerard Evan, Cancer Research UK’s co-leader of the ‘Dream Team’ and cancer gene expert at the University of Cambridge (link is external), said: "Despite the apparent diversity in pancreatic cancer, there are remarkable similarities in the biological pathways behind pancreatic tumours. Our goal is to exploit these to identify common targets for the development of more accurate and effective treatments for patients affected by this awful disease."

Around 8,500 in the UK and an estimated 40,000 people in the US will die from pancreatic cancer this year. The disease is the seventh leading cause of cancer death worldwide.

Professor Daniel Von Hoff, director of translational research at the Translational Genomics Research Institute (link is external), Arizona, who is leading the research team, said: "We’re going after pancreatic cancer in a different way. We will use new and existing drugs to reprogramme the master regulatory biological machinery in cancer cells that drives tumour growth. This machinery comprises molecular complexes of DNA and proteins that are known as ‘super enhancers’ for their ability to coordinate the expression of a large number of genes.

"By resetting the malfunctioning genome in both pancreatic tumour cells as well as the surrounding non-cancer cells on which the cancer cells rely for support, the team will try to increase the sensitivity of tumours to chemotherapy and make them vulnerable to the patient’s immune response."

Kerri Kaplan, executive director and chief operating officer of The Lustgarten Foundation, said: "To eradicate pancreatic cancer will take a collaborative effort and private funding plays a critical role in accelerating the development of new clinical trials for this deadly disease. This international collaboration will bring together leading global experts in the field of pancreatic cancer research, and together, we will focus on developing new therapies and innovative approaches so patients can benefit and live longer lives."

Dr Iain Foulkes, Cancer Research UK’s executive director of research funding, said: "Survival from pancreatic cancer is low – only three percent of patients in the UK survive their disease for five years or more. Frankly, progress has not been good enough and it’s why we have invested nearly £4 million in this ‘Dream Team’. These are among the finest researchers in the world and we’re really excited by the potential of their ideas in the fight against this terrible disease."

(Filing, 10-Q, Clovis Oncology, NOV 6, 2015, View Source [SID:1234508075])

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On November 6, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported data on the benefit of VAL-083 (dianhydrogalactitol) in combination with platinum-based chemotherapy regimens in the treatment of non-small cell lung cancer (NSCLC) (Press release, DelMar Pharmaceuticals, NOV 6, 2015, View Source [SID:1234508076]).

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"We have recently shown that VAL-083’s mechanism is distinct from platinum-based chemotherapy, the current standard of care for NSCLC, and is active against platinum and TKI-resistant NSCLC in both in vitro and in vivo models of lung cancer," stated Jeffrey Bacha, DelMar’s president and CEO. "The data presented today further demonstrate the non-overlapping mode of action between the platinum drugs and VAL-083 and the potential for treatment synergy in combination with therapeutic regimens."

The Company presented results from a collaborative study on the potential of VAL-083 in NSCLC in a poster entitled, "Dianhydrogalactitol (VAL-083) enhances activity of platinum drugs in non-small cell lung cancer," at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), hosted by American Association for Cancer Research (AACR) (Free AACR Whitepaper), the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer. The study was conducted in conjunction with research teams at MD Anderson Cancer Center, Shanghai Chest Hospital, and the BC Cancer Agency.

NSCLC is generally treated with surgery followed by chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but long term prognosis is poor. VAL-083 is a "first-in-class" bi-functional alkylating agent with proven activity against NSCLC in preclinical and clinical studies that meditates inter-strand DNA crosslinks at N7 of guanine.

VAL-083 demonstrated clinical activity as a single agent and in combination therapy in prior clinical trials sponsored by the US National Cancer Institutes (NCI) and has been approved by the Chinese Food and Drug Administration (CFDA) for the treatment of lung cancer. Use of VAL-083 in China has been limited by a lack of modern data and preference for targeted therapies, such as TKIs, in the modern era.

The results of the study presented at AACR (Free AACR Whitepaper)-NCI-EORTC support VAL-083 as a viable treatment option for NSCLC patients who fail to respond to standard-of-care platinum-based therapy or TKI therapy, and also support potential therapeutic benefit of a VAL-083 along with platinum combination regimens in newly diagnosed patients:

VAL-083 demonstrated cytotoxic activity in all tested NSCLC cell lines, including TKI-resistant cell lines;
VAL-083 demonstrated super-additivity/synergy against NSCLC cell lines H460, A549 and H1975 when combined with either cisplatin or oxaliplatin, in vitro;
VAL-083 is less dependent on p53 for its activity than both cisplatin and oxaliplatin, and appears to have a distinct mode of action in comparison to platinum-based chemotherapy; and
The combination of VAL-083 with cisplatin significantly decreased tumor growth and increased median survival time in a xenograft A549 in vivo model of NSCLC.

"These data are aligned with our strategy to leverage VAL-083’s established clinical activity with modern biologic research to target specific, underserved markets where resistance to current standard-of-care is correlated with poor patient outcomes. This tactic establishes a personalized-medicine approach based on a potent and broadly-active chemotherapy to address significant unmet medical needs in the modern treatment of cancer," Mr. Bacha added.

SUMMARY

The purpose of the in vitro portion of this study was to investigate: 1) the role of p53 status in VAL-083 activity; 2) VAL-083 cytotoxicity in a panel of NSCLC cell lines; and 3) the combination of VAL-083 with cisplatin or oxaliplatin in NSCLC cells.

Additionally, the combination of VAL-083 with cisplatin in NSCLC was also studied in vivo. Dependence on p53 status was investigated in isogenic HCT-116p53-/- and HCT-116p53+/+ models. VAL-083, cisplatin and oxaliplatin cytotoxicity was tested in a panel of nine (9) human NSCLC cell lines: four (4) wt, four (4) mutant and one (1) null for p53. The combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in three (3) human NSCLC cell lines, H460 (p53wt), A549 (p53wt) and H1975 (p53mut), by determining super-additivity and synergy using the criteria of combination index (CI)<1.

VAL-083 showed cytotoxic activity against all NSCLC cell lines in a human NSCLC panel, including TKI-resistant cell lines
VAL-083, cisplatin and oxaliplatin were tested in a panel of nine (9) human NSCLC cell lines, of which four (4) were wild-type p53 (H460, A549, H838, H226), four (4) were mutant p53 (H1975, SkLU1, H2122, H157) and one (1) was null for p53 (H1299). VAL-083 was active against all tested NSCLC cell lines, including TKI-resistant cell lines H1975, H460, and H1299, and VAL-083 activity was independent of p53 status.

VAL-083 mechanism is less dependent on p53

The dependence on p53 status was investigated in isogenic models with (HCT-116p53-/-) or without (HCT-116p53+/+) p53 knockout. Loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, whereas the increase in resistance to VAL-083 was <2-fold. This suggests a mechanism of VAL-083 that is less dependent on wild-type p53.

VAL-083 displays synergy in combination with cisplatin or oxaliplatin in NSCLC cells H460, A549 and H1975, in vitro
The combination of VAL-083 with either cisplatin or oxaliplatin in three human NSCLC cell lines demonstrated significant super-additivity (p≤0.06) and/or synergism (CI<1) for both combinations, in vitro. Significantly, this cytotoxic effect of VAL-083 in combination with either platinum drug was observed in both TKI-resistant (H1975 and H460) and TKI-sensitive (A549) NSCLC cells, irrespective of their p53 status. These results suggest non-overlapping mechanism of action between the platinum drugs and VAL-083, and support the potential for synergistic benefit for a combination of VAL-083 and platinum-based therapies in the treatment of lung cancer, including TKI-resistant NSCLC.

VAL-083/cisplatin combination increase median survival time in A549 NSCLC model, in vivo
Rag2 mice bearing A549 xenograft tumors were treated with vehicle, 2 mg/kg cisplatin alone, or cisplatin in combination with VAL-083 (2, 2.5, or 3 mg/kg). VAL-083 in combination with cisplatin significantly and dose-dependently decreased tumor growth in the animals and increased median survival time compared to both cisplatin treatment alone and to untreated control.

Mr. Bacha added, "We continue to build a significant portfolio of data demonstrating the activity of VAL-083 against a range of tumors, independent of their p53 status. These data taken together with the historical clinical activity support the potential of VAL-083 in NSCLC. An important next step will be to initiate new clinical studies to validate the clinical activity of VAL-083 in patients with relapsed or refractory NSCLC who currently have a lack of treatment options and poor prognosis."

"Interestingly, recent literature also correlate p53 mutations with high expression of MGMT and poor outcomes in the treatment of glioblastoma multiforme (GBM). Therefore, this latest research likewise supports the potential of our ongoing clinical research with VAL-083 as a potential new therapy in the treatment of refractory GBM," concluded Mr. Bacha.

The poster highlighting the potential of VAL-083 in NSCLC may be found on DelMar’s website under View Source

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.