On November 18, 2014 Agios Pharmaceuticals reported the first reported safety and clinical activity for AG-120 from the ongoing Phase 1 dose escalation study in patients with IDH1-mutant positive advanced hematologic malignancies, including acute myeloid leukemia (AML) (Press release Agios Pharmaceuticals, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990940 [SID:1234500982]). Agios has exclusive U.S. development and commercial rights to AG-120, a first-in-class, oral, selective, potent inhibitor of the mutant IDH1 enzyme. Daniel Pollyea, M.D., clinical investigator at the University of Colorado School of Medicine, will present the data in a late-breaking oral presentation today at the 26th Annual EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics being held in Barcelona, Spain. The company will webcast an investor conference call from the symposium at 10:00 a.m. EST (4:00 p.m. CET) on Wednesday, November 19, 2014.

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As of October 17, 2014, the ongoing Phase 1 trial for AG-120 had enrolled 17 patients with a documented IDH1 mutation whose cancer relapsed or failed to respond (refractory) to at least one prior treatment regimen. At the time of the data cut, 14 patients with relapsed and/or refractory AML were evaluable; three patients recently initiated therapy and were not evaluable.

The initial data showed investigator assessed objective responses in seven out of 14 evaluable patients, including four complete remissions, with responses observed across the four dose levels tested, and early evidence of durability. One additional patient remains stable on study. AG-120 was well tolerated, with the majority of adverse events reported as mild to moderate. The maximum tolerated dose has not yet been reached. One patient had a dose limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 after AG-120 dose reduction according to treatment protocol. This patient is in complete remission and remains on AG-120. AG-120 showed favorable drug exposure and pharmacokinetics at all doses tested and also substantially reduced plasma levels of the oncometabolite 2-hydroxyglutarate (2HG), which is produced by the mutant IDH1 protein, to the level observed in healthy volunteers. The mechanism of response is consistent with differentiation, as evidenced by the maturation of the leukemic cells into infection fighting white blood cells, or neutrophils. Based on these findings, the company plans to initiate multiple expansion cohorts in the first half of 2015.

"These data show very promising evidence of clinical activity for AG-120 in AML patients with an IDH1 mutation," said Chris Bowden, M.D., chief medical officer of Agios Pharmaceuticals. "Together with the data we reported from our ongoing Phase 1 study of AG-221 in advanced hematologic cancers, our lead investigational medicine and an IDH2-mutant inhibitor, we believe IDH inhibitors could potentially change the treatment paradigm for AML patients with these mutations. We look forward to moving rapidly into multiple expansion cohorts in the first half of 2015 to further characterize the potential of AG-120."

"We are highly encouraged to see the early favorable safety profile and clinical activity of AG-120, which includes four patients who achieved complete remission," said Dr. Pollyea. "For the first time in decades, we have the potential to offer certain AML patients an improved targeted treatment for this fatal disease that has historically had limited treatment options. I am hopeful that in the future we clinicians will be able to offer well tolerated and highly effective targeted therapies for our patients who have AML harboring an IDH mutation."

Patients in the ongoing Phase 1 trial have advanced AML whose cancer was refractory to available medical treatments or relapsed after treatment. The primary objectives of the Phase 1 trial are to determine the maximum tolerated dose (MTD) and the recommended dose for further study of AG-120. Secondary objectives include characterization of the safety profile, pharmacokinetics, pharmacodynamics and early anti-tumor activity. The trial uses an open-label, dose escalating design. Patients have been enrolled to date in four cohorts of AG-120 administered at 100 mg twice a day, 300 mg once a day, 500 mg once a day and 800 mg once a day. The median age of these patients is 73 (range 42-87).

On November 18, 2014 3SBio reported it has entered into an exclusive license with PharmAbcine, Inc. for the development, manufacturing and marketing of Tanibirumab, an anti-VEGFR2/KDR antibody for cancer in the territory of Greater China (including Mainland China, Taiwan, Hong Kong and Macau) and several emerging countries, including Thailand, Brazil and Russia (Press release 3SBio, NOV 18, 2014, View Source [SID:1234501350]). The deal included undisclosed upfront, milestone and royalty payments.

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Angiogenesis is correlated with disease progression and poor prognosis in many tumor types, such as colon, lung, breast and gastric cancers. VEGF and KDR (VEGFR2) are over-expressed in most malignant tumors, such as gastric, liver, NSCLC, ovarian, brain, colorectal, and breast cancers and their signaling is key regulator for tumor angiogenesis. Researchers from PharmAbcine have developed Tanibirumab, an anti-VEGFR2/KDR fully human monoclonal antibody to treat solid tumors. Tanibirumab binds KDR and blocks binding of VEGFR ligands, including VEGF-A, VEGF-C and VEGF-D. Consequently, Tanibirumab inhibits ligand-stimulated activation of KDR, therefore inhibits ligand-induced angiogenesis, proliferation, and migration of human endothelial cells.

Tanibirumab had demonstrated anti-angiogenic efficacy against several cancer types and shown cross-species cross reactivity in multiple preclinical animal models including breast cancer, glioblastoma (GBM), lung cancer, colon cancer, and hepatocellular carcinoma (HCC). In November 2011, an open-label, non-randomized, dose-escalating phase I trial began to assess the safety and pharmacokinetics of Tanibirumab, administered intravenously, in 26 patients in Korea with advanced or metastatic cancer. The trial was finished in November 2013, with good safety and efficacy results. A phase II study of Tanibirumab in GBM is being planned.

"We are pleased to collaborate with PharmAbcine and look forward to moving Tanibirumab into clinical trials in China," Dr. Jing Lou, President and CEO of 3SBio commented, "3SBio continues to seek opportunities to expand our biologics pipeline, especially novel mAb candidates for refractory or metastatic cancers and other unmet medical needs, particularly in 3SBio’s core therapeutic areas of oncology and nephrology."

"Tanibirumab is a drug candidate with great potential to treat malignant tumors," Dr. Jin-San Yoo, President and CEO of PharmAbcine commented, "3SBio is a well-established industry leader with long-term vision in the innovative biological field in China, which makes them an ideal partner for strategic collaborations. We are looking forward to working with 3SBio to maximize this opportunity and benefit tens of thousands of Chinese patients suffering for cancers and other severe diseases."

Each year, over 1 million patients are diagnosed with various types of cancer in China1.

On November 17, 2014 Kite Pharma reported that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending KTE-C19 for designation as an orphan medicinal product for the treatment of diffuse large B cell lymphoma (DLBCL) (Press release Kite Pharma, NOV 17, 2014, View Source [SID:1234501041]). KTE-C19 is an anti-CD19 CAR T cell therapy that involves genetically modifying a patient’s T cells to express a CAR that is designed to target CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

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The COMP, a committee of the EMA, adopts an opinion on the granting of orphan drug designation, after which the opinion is submitted to the European Commission for endorsement of the opinion. Orphan drug designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (EU), and where no satisfactory treatment is available. In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase, and direct access to the centralized authorization procedure.

DLBCL is an aggressive type of non-Hodgkin lymphoma for which the treatment options include chemotherapy, anti-CD20 antibodies, and, in selected patients, autologous transplant. Although most patients with DLBCL can be cured by either chemotherapy or transplant, a significant proportion of patients have disease that is resistant to chemotherapy or that relapses after transplant. For these patients with refractory DLBCL, there is a substantial unmet need for more effective therapies.

On November 17, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data that demonstrated that altiratinib (DCC-2701) inhibited tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model (Press release Deciphera Pharmaceuticals, NOV 17, 2014, View Source [SID:1234500972]). Altiratinib, a kinase inhibitor that targets multiple selected kinases MET, TIE2, VEGFR2 and TRK, is currently in Phase 1 clinical development for the treatment of invasive solid tumors and received Orphan Drug Status from the U.S. Food and Drug Administration for the treatment of glioblastoma. The data on altiratinib were presented at the 19th Annual Scientific Meeting and Education Day of The Society for Neuro-Oncology held November 13-16, 2014, in Miami.

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"Altiratinib is differentiated in its ability to inhibit MET and TRK kinases while also providing balanced inhibition of the tumor microenvironment within a single oral therapeutic," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "This balanced inhibitory profile demonstrates the power of Deciphera’s switch pocket technology to design advanced kinase inhibitor therapies to simultaneously block multiple cancer signaling mechanisms in the tumor cell and the tumor microenvironment to prevent growth and spread of cancer."
"These data demonstrated that altiratinib inhibited tumor growth and invasion both in vitro and in vivo. Based on these results, we believe the combination of altiratinib and anti-VEGF therapy may provide a new strategy to overcome antiangiogenic therapy resistance and prolong overall survival in patients with glioblastoma," said John F. de Groot MD, Associate Professor, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center and presenting author. "We look forward to further exploring the potential of altiratinib in refractory glioblastoma, an area of significant unmet medical need."

In an oral presentation titled, "The Novel c-MET inhibitor altiratinib (DCC-2701) inhibits tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model," John F. de Groot, MD and colleagues from the Brain Tumor Center at MD Anderson Cancer Center described data that demonstrated altiratinib, either alone or in combination with anti-VEGF therapy (bevacizumab), inhibited tumor growth, epithelial-mesenchymal transition (EMT) progression and invasion both in vitro and in vivo, compared with anti-VEGF therapy alone:

• Altiratinib, alone or in combination with bevacizumab treatment, dramatically suppressed EMT and tumor invasion in vivo. This anti-invasive effect correlated with decreased N-cadherin and vimentin levels.

• In vivo, microvascular density associated with evasive revascularization induced by bevacizumab, was significantly inhibited in the groups treated with altiratinib and altiratinib plus bevacizumab, compared with control or the group treated with bevacizumab alone.

• Similarly, F4/80+ bone marrow derived macrophage cell infiltration was significantly suppressed in the groups treated with altiratinib and altiratinib plus bevacizumab, compared to control or the group treated with bevacizumab alone.

Cancer, head and neck; Cancer, melanoma; Cancer, skin
It is in a multi-centre, single-agent, open-label, Phase I dose-escalation extension study to evaluate the safety and tolerability of repeated administrations of EBC-46 in patients who have successfully completed the main protocol (QB46C-H01, ANZCTR Trial ID: ACTRN12614000685617) (Clinical trial, Trial ID:ACTRN12614001207606, ANZCTR, NOV 17, 2014, View Source [SID1234517424]).
Patients will undergo a screening visit up to 3 months after completing the QB46C-H01 study. Treatment will be a single dose administered via intratumoural injection with safety monitoring for 21 days. Patients will be required to return for follow up assessments on Day 2, Day 8 (plus or minus 1 day), Day 15 (plus or minus 1 day) and Day 22 (plus or minus 1 day). Treatments will continue no sooner than 1 week since the last injection and will conclude when disease progression or intolerance presents.
Patients will initially receive the same dose level as they received in QB46C-H01 (if tolerated) or lower (if not tolerated or there is less tumour mass requiring dosing). Lower doses will be considered for patients who experienced a dose limiting toxicity (DLT) or Grade > 3 adverse event (AE) in the QB46C-H01 study or if the tumour burden requires less EBC-46.
The dose may be escalated to a higher level if that higher dose level has been demonstrated to be well-tolerated in the QB46C-H01 study (based on the incidence and severity of AEs and DLTs in the QB46C-H01 study) as determined by the Safety Review Committee.

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