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BURLINGTON, Mass., TOKYO, MUNICH, & PARSIPPANY, N.J.--(BUSINESS WIRE)--ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo today announced that the METIV-HCC phase 3 study of tivantinib in hepatocellular carcinoma (HCC) did not meet its primary endpoint of improving overall survival. METIV-HCC is a biomarker-selected, double-blind, placebo-controlled, randomized phase 3 study evaluating tivantinib (2:1) versus best supportive care in patients with MET-overexpressing, inoperable HCC intolerant to or previously-treated with systemic therapy. A total of 340 patients with MET-overexpressing HCC analyzed by a validated immunohistochemical assay were randomized in the intent-to-treat population for efficacy analysis. The primary endpoint of the study is overall survival. Secondary endpoints include progression-free survival and safety. Full results from the trial will be presented at an upcoming scientific forum. “HCC is a disease with high unmet need, especially in the second-line setting, so these results are disappointing for the patients as well as the investigators and the companies,” said Paolo Pucci, Chief Executive Officer of ArQule. “Despite the negative outcome of this study, we remain committed to applying rigorous science to unmet needs for patients with cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. “We would like to take this opportunity to thank all of the investigators, and especially the patients, for their participation in this study.” The ArQule investor conference call can be accessed in the “Investors and Media” section of ArQule’s website, www.arqule.com, under “Events and Presentations.” You may also listen to the call by dialing (877) 868-1831 within the U.S. or (914) 495-8595 outside the U.S. and using the passcode 74015633. A replay will be available two hours after the completion of the call and can be accessed in the “Investors and Media” section of our website, www.arqule.com, under “Events and Presentations.” About Hepatocellular Carcinoma (HCC) Liver cancer is the sixth most common cancer globally with 782,000 new cases in 2012 and is the second most common cause of cancer-related death with 745,000 deaths in 2012.1 HCC accounts for about 90 percent of primary liver cancers.2 Cirrhosis, chronic hepatitis B and C and smoking are recognized worldwide as factors increasing the risk of HCC.2 About Tivantinib (ARQ 197) ArQule and Daiichi Sankyo have a licensing, co-development and co-commercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan. About ArQule ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases. Our mission is to discover, develop and commercialize novel small molecule drugs in areas of high unmet need that will dramatically extend and improve the lives of our patients. Our clinical-stage pipeline consists of five drug candidates, all of which are in targeted, biomarker-defined patient populations, making ArQule a leader among companies our size in precision medicine. ArQule’s lead product, in phase 3 clinical development, is tivantinib (ARQ 197), an oral, selective inhibitor of the c-MET receptor tyrosine kinase, for second-line treatment of patients with MET-overexpressing hepatocellular carcinoma in partnership with Daiichi Sankyo in the West and Kyowa Hakko Kirin in Asia. ArQule’s proprietary pipeline includes: ARQ 087, a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family, in phase 2 for iCCA and in phase 1b for multiple oncology indications; ARQ 092, a selective inhibitor of the AKT serine/threonine kinase, in phase 1 for multiple oncology indications as well as ultra-rare Proteus syndrome, in partnership with the National Institutes of Health (NIH); ARQ 751, a next generation AKT inhibitor, in phase 1 for patients with AKT1 and PI3K mutations; and ARQ 761, a β-lapachone analog being evaluated as a promoter of NQO1-mediated programmed cancer cell necrosis, in phase 1/2 in multiple oncology indications in partnership with the University of Texas Southwestern Medical Center. In addition, we have advanced ARQ 531, an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant BTK, into toxicology testing and plan to file an Investigational New Drug Application in early 2017. ArQule’s current discovery efforts are focused on the identification and development of novel kinase inhibitors, leveraging the Company’s proprietary library of compounds. You can follow us on Twitter and LinkedIn. About Daiichi Sankyo Cancer Enterprise The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for FLT3-ITD+ AML; DS-8201, a HER2-targeting ADC, for HER2-expressing breast or gastric cancer or other HER2-expressing solid tumors; pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy, pembrolizumab; and tivantinib, an oral MET inhibitor, for second-line treatment of patients with MET-overexpressing hepatocellular carcinoma in partnership with ArQule, Inc. About Daiichi Sankyo Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for hypertension and thrombotic disorders, under the Group’s 2025 Vision to become a “Global Pharma Innovator with a Competitive Advantage in Oncology,” Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit: www.dsi.com. This press release contains forward-looking statements regarding the Company's clinical trials with tivantinib (ARQ 197). These statements are based on the Company's current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about pre-clinical and early stage clinical trial results does not ensure that later stage or larger scale clinical trials will be successful. For example, tivantinib may not demonstrate promising therapeutic effect or appropriate safety profiles in current or later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards or to justify further development. Problems or delays may arise prior to the initiation of planned clinical trials, during clinical trials or in the course of developing, testing or manufacturing that could lead the Company or its partners and collaborators to fail to initiate or to discontinue development. Even if later stage clinical trials are successful, unexpected concerns may arise from subsequent analysis of data or from additional data. Obstacles may arise or issues may be identified in connection with review of clinical data with regulatory authorities. Regulatory authorities may disagree with the Company's view of the data or require additional data or information or additional studies. In addition, the planned timing of initiation and completion of clinical trials for tivantinib is subject to the ability of the Company as well as Daiichi Sankyo, Inc., our development partner for tivantinib, and Kyowa Hakko Kirin, a licensee of tivantinib, to enroll patients, enter into agreements with clinical trial sites and investigators, and overcome technical hurdles and other issues related to the conduct of the trials for which each of them is responsible. There is a risk that these issues may not be successfully resolved. In addition, we and our partners are utilizing companion diagnostic tests to identify MET-overexpressing patients in the METIV-HCC, JET-HCC and other trials. We may encounter difficulties in developing and obtaining approval for companion diagnostics, including issues relating to selectivity/specificity, analytical validation, reproducibility, or clinical validation. Any delay or failure by our collaborators or us to develop or obtain regulatory approval of the companion diagnostics could delay or prevent approval of our product candidates. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product. Positive pre-clinical data may not be supported in later stages of development. Furthermore, ArQule may not have the financial or human resources to successfully pursue drug discovery in the future. Moreover, with respect to partnered programs, even if certain compounds show initial promise, Daiichi Sankyo or Kyowa Hakko Kirin may decide not to license or continue to develop them, as the case may be. In addition, Daiichi Sankyo and Kyowa Hakko Kirin have certain rights to unilaterally terminate their agreements with ArQule. If either company were to do so, the Company might not be able to complete development and commercialization of the applicable licensed products on its own. For more detailed information on the risks and uncertainties associated with the Company's drug development and other activities, see the Company's periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forward-looking statements.


ArQule to host investor conference call on February 17, 2017 at 8:30 A.M. ET BURLINGTON, Mass. and TOKYO and MUNICH and PARSIPPANY, N.J., Feb. 17, 2017 /PRNewswire/ -- ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo today announced that the METIV-HCC phase 3 study of tivantinib in hepatocellular carcinoma (HCC) did not meet its primary endpoint of improving overall survival. METIV-HCC is a biomarker-selected, double-blind, placebo-controlled, randomized phase 3 study evaluating tivantinib (2:1) versus best supportive care in patients with MET-overexpressing, inoperable HCC intolerant to or previously-treated with systemic therapy. A total of 340 patients with MET-overexpressing HCC analyzed by a validated immunohistochemical assay were randomized in the intent-to-treat population for efficacy analysis. The primary endpoint of the study is overall survival. Secondary endpoints include progression-free survival and safety. Full results from the trial will be presented at an upcoming scientific forum. "HCC is a disease with high unmet need, especially in the second-line setting, so these results are disappointing for the patients as well as the investigators and the companies," said Paolo Pucci, Chief Executive Officer of ArQule. "Despite the negative outcome of this study, we remain committed to applying rigorous science to unmet needs for patients with cancer," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "We would like to take this opportunity to thank all of the investigators, and especially the patients, for their participation in this study." The ArQule investor conference call can be accessed in the "Investors and Media" section of ArQule's website, www.arqule.com, under "Events and Presentations." You may also listen to the call by dialing (877) 868-1831 within the U.S. or (914) 495-8595 outside the U.S. and using the passcode 74015633. A replay will be available two hours after the completion of the call and can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events and Presentations." About Hepatocellular Carcinoma (HCC) Liver cancer is the sixth most common cancer globally with 782,000 new cases in 2012 and is the second most common cause of cancer-related death with 745,000 deaths in 2012.1 HCC accounts for about 90 percent of primary liver cancers.2 Cirrhosis, chronic hepatitis B and C and smoking are recognized worldwide as factors increasing the risk of HCC.2 About Tivantinib (ARQ 197) ArQule and Daiichi Sankyo have a licensing, co-development and co-commercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan. About ArQule ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases. Our mission is to discover, develop and commercialize novel small molecule drugs in areas of high unmet need that will dramatically extend and improve the lives of our patients. Our clinical-stage pipeline consists of five drug candidates, all of which are in targeted, biomarker-defined patient populations, making ArQule a leader among companies our size in precision medicine. ArQule's lead product, in phase 3 clinical development, is tivantinib (ARQ 197), an oral, selective inhibitor of the c-MET receptor tyrosine kinase, for second-line treatment of patients with MET-overexpressing hepatocellular carcinoma in partnership with Daiichi Sankyo in the West and Kyowa Hakko Kirin in Asia. ArQule's proprietary pipeline includes: ARQ 087, a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family, in phase 2 for iCCA and in phase 1b for multiple oncology indications; ARQ 092, a selective inhibitor of the AKT serine/threonine kinase, in phase 1 for multiple oncology indications as well as ultra-rare Proteus syndrome, in partnership with the National Institutes of Health (NIH); ARQ 751, a next generation AKT inhibitor, in phase 1 for patients with AKT1 and PI3K mutations; and ARQ 761, a β-lapachone analog being evaluated as a promoter of NQO1-mediated programmed cancer cell necrosis, in phase 1/2 in multiple oncology indications in partnership with the University of Texas Southwestern Medical Center. In addition, we have advanced ARQ 531, an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant BTK, into toxicology testing and plan to file an Investigational New Drug Application in early 2017. ArQule's current discovery efforts are focused on the identification and development of novel kinase inhibitors, leveraging the Company's proprietary library of compounds. You can follow us on Twitter and LinkedIn. About Daiichi Sankyo Cancer Enterprise The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for FLT3-ITD+ AML; DS-8201, a HER2-targeting ADC, for HER2-expressing breast or gastric cancer or other HER2-expressing solid tumors; pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy, pembrolizumab; and tivantinib, an oral MET inhibitor, for second-line treatment of patients with MET-overexpressing hepatocellular carcinoma in partnership with ArQule, Inc. About Daiichi Sankyo Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for hypertension and thrombotic disorders, under the Group's 2025 Vision to become a "Global Pharma Innovator with a Competitive Advantage in Oncology," Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit: www.dsi.com. This press release contains forward-looking statements regarding the Company's clinical trials with tivantinib (ARQ 197). These statements are based on the Company's current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about pre-clinical and early stage clinical trial results does not ensure that later stage or larger scale clinical trials will be successful. For example, tivantinib may not demonstrate promising therapeutic effect or appropriate safety profiles in current or later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards or to justify further development. Problems or delays may arise prior to the initiation of planned clinical trials, during clinical trials or in the course of developing, testing or manufacturing that could lead the Company or its partners and collaborators to fail to initiate or to discontinue development. Even if later stage clinical trials are successful, unexpected concerns may arise from subsequent analysis of data or from additional data. Obstacles may arise or issues may be identified in connection with review of clinical data with regulatory authorities. Regulatory authorities may disagree with the Company's view of the data or require additional data or information or additional studies. In addition, the planned timing of initiation and completion of clinical trials for tivantinib is subject to the ability of the Company as well as Daiichi Sankyo, Inc., our development partner for tivantinib, and Kyowa Hakko Kirin, a licensee of tivantinib, to enroll patients, enter into agreements with clinical trial sites and investigators, and overcome technical hurdles and other issues related to the conduct of the trials for which each of them is responsible. There is a risk that these issues may not be successfully resolved. In addition, we and our partners are utilizing companion diagnostic tests to identify MET-overexpressing patients in the METIV-HCC, JET-HCC and other trials. We may encounter difficulties in developing and obtaining approval for companion diagnostics, including issues relating to selectivity/specificity, analytical validation, reproducibility, or clinical validation. Any delay or failure by our collaborators or us to develop or obtain regulatory approval of the companion diagnostics could delay or prevent approval of our product candidates. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product. Positive pre-clinical data may not be supported in later stages of development. Furthermore, ArQule may not have the financial or human resources to successfully pursue drug discovery in the future. Moreover, with respect to partnered programs, even if certain compounds show initial promise, Daiichi Sankyo or Kyowa Hakko Kirin may decide not to license or continue to develop them, as the case may be. In addition, Daiichi Sankyo and Kyowa Hakko Kirin have certain rights to unilaterally terminate their agreements with ArQule. If either company were to do so, the Company might not be able to complete development and commercialization of the applicable licensed products on its own. For more detailed information on the risks and uncertainties associated with the Company's drug development and other activities, see the Company's periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forward-looking statements.


Poster presentations also will highlight preclinical data examining the role of DS-8201 in combination with immunotherapy, the study design of the phase 1 study of U3-1402 in patients with HER3-expressing metastatic breast cancer and patient-reported outcomes in a phase 1 study of pexidartinib in tenosynovial giant cell tumor (TGCT), which includes pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS). "These presentations continue to underscore the promise of DS-8201 and U3-1402, which employ our unique ADC technology, to potentially change the standard of care in both HER2-expressing and HER3-expressing metastatic breast cancer," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "In the context of recent advances made in the field of molecularly targeted new science for breast cancer, our own research further contributes to providing advanced or metastatic breast cancer with precision medicine options." DS-8201, U3-1402, pexidartinib and tivantinib have not been approved for any indication in any country. About DS-8201 and U3-1402 Antibody drug conjugates (ADCs) are a type of targeted cancer medicine that deliver cytotoxic chemotherapy ("payload") directly to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. DS-8201 and U3-1402 are ADCs that use Daiichi Sankyo's proprietary payload and linker-payload technology, which has broad application across multiple types of cancer, and are designed to deliver enhanced cancer cell destruction with less systemic exposure to the cytotoxic payload. DS-8201 is an investigational ADC currently in phase 1 clinical development for HER2-positive advanced or metastatic breast cancer or gastric cancer, HER2-low-expressing breast cancer and other HER2-expressing solid cancers. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to DS-8201 for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including ado-trastuzumab emtansine (T-DM1). U3-1402 is an investigational and potential first-in-class ADC currently in phase 1 clinical development for HER3-expressing metastatic or unresectable breast cancer. About Pexidartinib Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF-1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo. Pexidartinib has been granted Breakthrough Therapy Designation for the treatment of TGCT and Orphan Drug Designation for PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Designation from the European Commission for the treatment of TGCT. Pexidartinib is also being evaluated in several additional potential clinical indications, including glioblastoma, melanoma, ovarian, colorectal and pancreatic cancer. It is also being investigated in combination with anti-PD-1 immunotherapy, pembrolizumab, for multiple tumor types, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer and gastrointestinal stromal tumors. About Daiichi Sankyo Cancer Enterprise The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) Franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for newly-diagnosed and relapsed/refractory AML with FLT3-ITD mutations; DS-8201, an ADC for HER2-expressing breast cancer, gastric cancer and other HER2-expressing solid tumors; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy pembrolizumab. For more information, please visit: www.DSCancerEnterprise.com. About Daiichi Sankyo Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for hypertension and thrombotic disorders, under the Group's 2025 Vision to become a "Global Pharma Innovator with a Competitive Advantage in Oncology," Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit: www.dsi.com. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/daiichi-sankyo-cancer-enterprise-pipeline-data-showing-swift-progress-in-precision-medicine-for-breast-cancer-to-be-presented-at-2017-american-society-of-clinical-oncology-asco-annual-meeting-300461748.html


- Preliminary results from a phase 1 study of MDM2 inhibitor DS-3032 in relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) to be presented - Monotherapy dosing strategy of FLT3 inhibitor quizartinib identified by laboratory and clinical investigations for FLT3-ITD+ AML - Development of DS-3032 and quizartinib underscores Daiichi Sankyo commitment to AML PARSIPPANY, New Jersey and MUNICH, Nov. 30, 2016 /PRNewswire/ -- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced that data from two of its investigational targeted therapies, DS-3032 and quizartinib, will be presented during the 58th Annual Meeting of the American Society of Hematology (ASH) taking place on December 3-6 in San Diego. Preliminary safety and efficacy phase 1 data on DS-3032, an investigational oral selective MDM2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) will be featured as an oral presentation. Data outlining the dosing strategy for quizartinib, an oral FLT3 inhibitor, in patients with relapsed/refractory FLT3-ITD+ AML also will be presented. "Given that there has been little change in the treatment of AML for the past 30 years, we are committed to identifying novel treatments that could potentially change the standard of care for these patients," said Ken Kobayashi, MD, Executive Director, Global Oncology Research and Development, Daiichi Sankyo. "We look forward to presenting the results of the DS-3032 and quizartinib studies to the scientific community at ASH." Abstract #593: Phase 1 Dose Escalation Study of MDM2 Inhibitor DS-3032 in Patients with Hematological Malignancies – Preliminary Results Preliminary results from the dose escalation part of a phase 1 study of DS-3032 will be part of an oral presentation session on Monday, December 5, 2016 from 7:00 AM-8:30 AM at the San Diego Ballroom AB (Marriott Marquis San Diego Marina). The primary objectives are to examine the safety and tolerability of DS-3032 and determine the maximum tolerated dose or tentative recommended phase 2 dose. Secondary objectives include evaluating the pharmacokinetics and pharmacodynamics effects of DS-3032. Exploratory objectives include evaluating the efficacy of DS-3032. Data on 38 patients with relapsed/refractory AML and high-risk MDS will be presented. Abstract#4042: Laboratory and Clinical Investigations to Identify the Optimal Dosing Strategy for Quizartinib (AC220) Monotherapy in FLT3-ITD–Positive (+) Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) An overview of pre-clinical, pharmacokinetic (PK) and clinical study results used to establish and justify monotherapy dosing strategy for quizartinib will be part of a poster session on Monday, December 5, 2016 from 6:00 PM-8:00 PM in Hall GH (San Diego Convention Center). This dosing strategy is currently being used in the phase 3 QuANTUM-R study examining the role of quizartinib monotherapy in patients with relapsed/refractory FLT3-ITD+ AML. DS-3032 and quizartinib have not been approved by any regulatory authority for uses under investigation. DS-3032 is an investigational oral selective inhibitor of the murine double minute 2 (MDM2) protein currently being investigated in three phase 1 clinical trials for solid and hematological malignancies including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma, and myelodysplastic syndrome (MDS). Quizartinib is an investigational oral FLT3 inhibitor currently being evaluated in two global, pivotal phase 3 trials in patients with newly-diagnosed (QuANTUM-First) and relapsed/refractory (QuANTUM-R) FLT3-ITD+ AML. Quizartinib has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of AML. Quizartinib has also been granted Fast Track Designation by the FDA for the treatment of relapsed/refractory AML. The vision of Daiichi Sankyo Cancer Enterprise is to push beyond traditional thinking to align world-class science to create innovative treatments for patients with cancer. The oncology pipeline of Daiichi Sankyo continues to grow and currently includes more than 20 small molecules, monoclonal antibodies and antibody drug conjugates with novel targets in both solid and hematological cancers. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML); pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), also known as pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS), which also is being investigated in combination with anti-PD1 immunotherapy, pembrolizumab, in a range of solid tumors; tivantinib, an oral MET inhibitor, for second-line treatment of patients with MET-high hepatocellular carcinoma in partnership with ArQule, Inc.; and DS-8201, a HER2 targeting antibody drug conjugate, for HER2-expressing breast or gastric cancer or other HER2-expressing solid tumors. Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for hypertension and thrombotic disorders, under the Group's 2025 Vision to become a "Global Pharma Innovator with a Competitive Advantage in Oncology," Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit: www.dsi.com. Intended for US and EU Medical Media Only


Coiffier B.,Hematology | Osmanov E.A.,Cancer Research Center | Hong X.,Fudan University | Scheliga A.,Instituto Nacional Of Cancer | And 15 more authors.
The Lancet Oncology | Year: 2011

Background: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m2, administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Findings: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc. © 2011 Elsevier Ltd.


Duchnowska R.,Military Institute of Medicine | Biernat M.,Medical University of Gdańsk | Szostakiewicz B.,Medical University of Gdańsk | Sperinde J.,Monogram Biosciences | And 16 more authors.
Oncologist | Year: 2012

Background. Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) inHER-2+ advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy forHER-2+ metastatic breast cancer. HER-2/ neu gene copy number was quantified as the HER-2/ centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab- containing therapy. Results. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p =.013, 28, and 25, respectively). In the subset of patients that was centrally determined by FISH to beHER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p =.005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p =.4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p =.024). Conclusions. These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse inHER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group. © AlphaMed Press.


Xu C.-F.,Glaxosmithkline | Reck B.H.,NC | Goodman V.L.,Oncology Research and Development | Xue Z.,NC | And 7 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. Methods: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. Results: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p <0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r2 = 0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6) × ULN for rs2858996 GG (n = 148), GT (n = 82), and TT (n = 1 2) genotypes, respectively. All 12 TT patients had a maximum ALT >ULN, and 8 (67%) had ALT ≥3 × ULN. The odds ratio (95% CI) for ALT ≥3 × ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT ≥3 × ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. Conclusions: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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