On August 27, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported 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) (Press release, Threshold Pharmaceuticals, AUG 27, 2015, View Source [SID:1234507345]). Tarloxotinib is Threshold’s proprietary, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand. Schedule your 30 min Free 1stOncology Demo! "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."
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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.
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1.The high expression level of full length human antibody in CHO cell line
2.Tumor angiogenesis specific mechanism and safe to healthy tissue
3.Broad-spectrum antitumor effect
Current stage: Preclinical study
Immatics and MD Anderson announce launch of Immatics US, Inc., to develop multiple T-cell and TCR-based adoptive cellular therapies
On August 26, 2015 Immatics Biotechnologies GmbH (Immatics) and The University of Texas MD Anderson Cancer Center reported the launch of Immatics US, Inc., a new company aiming at becoming a global leader in adoptive cellular therapies (ACT) for the treatment of a range of tumor types (Press release, immatics biotechnologies, AUG 26, 2015, View Source [SID:1234514979]).
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Immatics believes that ACT approaches to be developed by the new company can achieve a step change in the treatment of cancer, by delivering significant, long- lasting clinical benefits. The new company will strive to develop three different ACT approaches for the treatment of tumors with high un-met medical needs, the first of which will enter the clinic in 2016.
Immatics US, Inc. will develop both autologous and allogenic ACT approaches by capitalizing on MD Anderson’s world-leading clinical oncology and cell therapy expertise and Immatics’ unrivaled cancer target and T-cell receptor (TCR) discovery capabilities.
Immatics US, Inc. will be based in Houston and has secured a first funding round totaling over $60m with more than $40m committed by the parent company Immatics Biotechnologies GmbH and $19.7 million by a recently awarded grant from the Cancer Prevention and Research Institute of Texas (CPRIT).
Immatics has been able to use its unique and world-leading technology platform XPRESIDENT for the discovery and further qualification of dozens of novel, proprietary and highly specific cancer targets that can be used as the basis for a range of cancer immunotherapy applications including ACT. This capability will enable Immatics US, Inc. to develop TCR-based approaches and to have complementary utility with other approaches for addressing tumor targets. Immatics believes its ACT will be both efficacious and safe due to the specificity of its novel well-characterized targets, including novel over-expressed, cancer-testis and neo-antigens ideally suited for specific and safe ACT approaches.
lmmatics has been benefiting from MDACC’s outstanding understanding of cancer immunotherapy. Two leading MD Anderson scientists, Patrick Hwu, M.D., Division Head of Cancer Medicine, and Cassian Yee, M.D., Professor of Medical Melanoma Oncology, have laid the scientific foundation for the adoptive cell therapy development plans of lmmatics US, Inc., and they will continue to provide ongoing practical support and guidance as the Company develops its ACT approaches and therapies.
Immatics has also gained access to various technologies developed or in-licensed by MD Anderson. These include the use of the cytokine IL-21 for expansion of T cells, a gamma-delta T-cell platform for allogeneic cell therapy approaches and various technologies designed to optimize the development of ACT.
"The potential of cancer immunotherapy has been constrained by the lack of novel targets. Immatics has been working for the last 15 years to gain a broad and in-depth understanding of the immunopeptidome of tumor and normal tissue cells," said Harpreet Singh, CEO of Immatics US, Inc. "Based on this unique expertise we have discovered dozens of novel immunotherapy targets that will be central to the success of Immatics US, Inc. With several complementary development programs guided by some of the most exceptional scientists in the field of cancer immunotherapy, we are in exactly the right place to deliver transforming therapies to cancer patients with high medical need."
"We are extremely excited about the potential of Immatics US, Inc. to develop and commercialize the world’s best ACT," said Paul Higham, CEO of the parent company Immatics. "The combination of MD Anderson’s significant clinical oncology and cell therapy expertise and our own unrivaled cancer target discovery capabilities will allow us to develop the optimal ACT for the treatment of cancer, initially a range of solid tumors with high un-met medical need. I would like to thank CPRIT and our investors for their financial support and look forward to developing Immatics US, Inc. into one of the world’s leading cancer immunotherapy companies."
"Our on-going efforts to provide the most innovative therapies to our patients are due, in part, to collaborations both in academia and industry," said Ronald DePinho, M.D., president of MD Anderson. "It is only through working with other leaders in cancer science will we provide the solutions of tomorrow."
Verastem Issues Statement Regarding WCLC Presentations
On August 26, 2015 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, today issued the following statement in response to inquiries regarding the anticipated oral presentation of VS-6063 (defactinib) data from a Phase 2 study in patients with KRAS mutant non-small cell lung cancer (NSCLC) at the 16th World Conference on Lung Cancer (WCLC):
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"While updated results from the Phase 2 study of VS-6063 in KRAS mutant non-small cell lung cancer are under embargo until WCLC, Verastem believes the study has met its goals, with encouraging outcomes that the Company plans to explore in future studies (Press release, Verastem, AUG 26, 2015, View Source;p=RssLanding&cat=news&id=2082284 [SID:1234507350]). The population explored in this study has refractory, advanced lung cancer, with a median of three prior therapies, and as many as eight prior therapies. The advanced stage of disease led, in some cases, to deaths even in the period between screening and prior to first dose of VS-6063. Two subjects reported as having grade 5 respiratory failure were on multiple concomitant medications and presented with multiple co-morbidities. Both were thoroughly evaluated and reported to the regulatory authorities in 2013 and 2014 when they occurred.
"The totality of safety and efficacy data seen to date with VS-6063 across multiple clinical trials, multiple tumor types and stages of treatment is promising. In addition, in the Company’s registration-directed COMMAND trial in mesothelioma, an independent data safety monitoring board has met and reviewed study data, including adverse events, three times and recommended no changes to study protocol. There have been over 300 patients treated to date with VS-6063, including patients on drug for more than one year. Verastem remains encouraged by the clinical potential of targeting cancer stem cells through FAK inhibition, and is unwavering in its commitment to delivering novel, safe and effective treatments to patients with unmet medical needs."
About VS-6063
VS-6063 (defactinib) is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). Cancer stem cells are an underlying cause of tumor resistance to chemotherapy, recurrence and ultimate disease progression. Research has demonstrated that FAK activity is critical for the growth and survival of cancer stem cells. VS-6063 is currently being studied in the registration-directed COMMAND trial in mesothelioma (www.COMMANDmeso.com), a "Window of Opportunity" study in patients with mesothelioma prior to surgery, a Phase 1/1b study in combination with paclitaxel in patients with ovarian cancer, a trial in patients with KRAS-mutated non-small cell lung cancer and a trial evaluating the combination of VS-6063 and VS-5584 in patients with relapsed mesothelioma. VS-6063 has been granted orphan drug designation for use in mesothelioma in the U.S. and EU.
Cellectis to Present Data on its CAR T-Cell Immunotherapy Programs During Upcoming Conferences
On August 26, 2015 Cellectis (Alternext: ALCLS – Nasdaq Global Market: CLLS), a pioneering gene-editing company employing proprietary technologies to develop best-in-class products in the emerging field of immuno-oncology, reported that pre-clinical data on its engineered allogeneic CAR T-cells will be featured during several conferences in the coming weeks (Press release, Cellectis, AUG 26, 2015, View Source [SID:1234507344]).
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The Immunotherapy and Vaccine Summit
August 24th to 28th, 2015, Boston, USA
• André Choulika, Ph.D., Chairman and CEO of Cellectis, will be presenting in the panel "Advantages and Disadvantages of Different Gene Editing Technologies" on Thursday, August 27th at 11:45AM.
• Dr Choulika will also give a presentation entitled "Allogeneic Universal CAR-T Cells Engineered With TALEN" during the session "Merging Gene Editing and Immunotherapy" on Thursday, August 27th at 3:05PM.
• Julien Valton, Ph.D., Senior Scientist at Cellectis, will give a presentation entitled "A Multidrug Resistant Engineered CAR T-Cell for Allogeneic Combination Immunotherapy" during the session "Chimeric Antigen Receptors" on Thursday, August 27th at 11:15AM.
CRI-CIMT-EATI-AACR Immunotherapy Conference
September 16th to 19th, 2015, New York, USA
• Laurent Poirot, Head of Early Discovery at Cellectis, to present a poster entitled "Targeted genome modifications for Improved Adoptive Immunotherapy" on Wednesday, September 16.
• Philippe Duchateau, Chief Scientific Officer at Cellectis, to present a poster entitled "Design of a chimeric antigen receptor (CAR) with controllable function via small molecule" on Friday, September 18.
• Julianne Smith, VP CAR T Development at Cellectis, to present a poster entitled "Allogeneic CAR T-cells for Adoptive Immunotherapy" on Friday, September 18.
Phacilitate Cell & Gene Therapy
September 29th to 30th, 2015, Barcelona, Spain
• Stéphan Reynier, Chief Regulatory and Compliance Officer at Cellectis, to present as a chairperson during the session: "What is the most realistic, practicable supply chain solution for this particular class of products in Europe? What would be most feasible for rare vs. common indications?" This roundtable discussion will take place on Wednesday, September 30th, from 4:20 to 5:30PM.