On January 4, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX) reported the opening of an investigator initiated Phase 2 study at the University of Nebraska Medical Center (UNMC) to evaluate the safety and efficacy of TGR-1202, the Company’s oral PI3K delta inhibitor in combination with ibrutinib, in patients with relapsed or refractory Diffuse Large B-cell Lymphoma (DLBCL) (Press release, TG Therapeutics, JAN 4, 2017, View Source [SID1234517258]). TG Therapeutics and Janssen Pharmaceuticals will each provide drug and equally share study-related costs.

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The rationale for combining these two agents is based on the prior clinical activity and tolerable safety profile observed with TGR-1202 both alone and in combination with ibrutinib in previous studies, as well as preclinical work conducted as part of a research collaboration with Dr. Michael Green and the University of Nebraska Medical Center’s Lymphoma Precision Medicine Laboratory in Omaha, NE. The combination of TGR-1202 and ibrutinib has been studied previously in patients with Chronic Lymphocytic Leukemia (CLL) and non-Hodgkin’s lymphoma, both with and without the addition of the anti-CD20 monoclonal antibody TG-1101 (ublituximab). Data on the combination of TGR-1202 plus ibrutinib were presented most recently at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) meeting, with data demonstrating an acceptable safety profile at full doses of both ibrutinib and TGR-1202.

The Phase 2 study will evaluate the safety and efficacy of the combination of TGR-1202 and ibrutinib, as well as explore correlative analyses related to the combination.

"We are excited to launch this study led by Drs. Matthew Lunning and Michael Green. Dr. Lunning has extensive experience treating lymphoma patients with TGR-1202 as a doublet in combination with TG-1101 and also as a triple therapy with ibrutinib. While the triple combination appears safe, well tolerated and active, looking at the effects of the all oral doublet combination will expand our understanding of the effects of these agents together and the contribution of TG-1101 in a triple combination," stated Michael S. Weiss, the Company’s Executive Chairman and Interim Chief Executive Officer.

"Success with small molecule inhibitors that abrogate the abnormal signaling through the BCR pathway observed in B-cell malignancies has brought upon an exciting paradigm shift in the management of B-cell NHL. However, DLBCL patients who relapse from transplant or are refractory to front-line or subsequent therapies continue to have a poor prognosis and new novel combinations are desperately needed. At present, targeted agents against the BCR pathway have been primarily explored as single agents or in combination with a CD20 monoclonal antibody. Based on the existing clinical data in other lymphomas and the exciting preclinical data completed here by my colleague Dr. Green at UNMC, we are excited to launch this novel chemo-free all oral combination trial of TGR-1202 and ibrutinib which may be an attractive combination for this difficult to treat patient population," stated Dr. Matthew Lunning of the Fred & Pamela Buffett Cancer Center, which is the National Cancer Institute-designated cancer center located on the campus of UNMC and its clinical partner, Nebraska Medicine, in Omaha, NE.

This study is currently open to enrollment. More information on this clinical study can be found at www.clinicaltrials.gov.

On January 4, 2016 Kura Oncology, Inc. (NASDAQ:KURA), a clinical stage biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) accepted the company’s Investigational New Drug (IND) application to begin Phase 1 clinical testing of KO-947, its small molecule inhibitor of extracellular-signal-regulated kinases 1 and 2 (ERK1/2) as a treatment for cancers in which the mitogen activated protein kinase (MAPK) pathway is dysregulated (Press release, Kura Oncology, JAN 4, 2017, View Source [SID1234517257]). Additionally, Kura announced nomination of KO-539, an orally-available small molecule inhibitor of the menin-MLL interaction, as a development candidate for the treatment of mixed lineage leukemias, a genetically-defined subset of the two most common forms of acute leukemia, acute myeloid leukemia and acute lymphoblastic leukemia.

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"We are delighted to reach these important milestones in the development of our pipeline programs. KO-947, our ERK inhibitor, has shown compelling and differentiated anti-tumor activity in preclinical models of cancers in which the MAPK pathway is dysregulated, and we look forward to advancing it into human clinical testing," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "We are also pleased to nominate KO-539, an inhibitor of the menin-MLL interaction, as a development candidate, which we are advancing as a potential treatment for patients with particularly aggressive forms of leukemia. Along with the progress we have made on tipifarnib, our lead program, these achievements are a testament to our team’s ability to execute on our stated goal of simultaneously advancing multiple programs aimed at addressing the urgent needs of cancer patients facing a poor prognosis and limited treatment options."

Kura expects to initiate a Phase 1 clinical trial of KO-947 in patients with a variety of solid tumors with dysregulation of the MAPK pathway in the first half of 2017. The company’s goal for its menin-MLL inhibitor program is to initiate a Phase 1 clinical trial in 2018.

On January 4, 2017 Bayer reported that the U.S. Food and Drug Administration (FDA) has granted priority review designation to the supplemental New Drug Application (sNDA) for regorafenib for the second-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) in the U.S (Press release, Bayer, JAN 4, 2017, View Source [SID1234517256]).

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"Liver cancer is one of the leading cancer-related causes of death world-wide and more than 30,000 cases of liver cancer are diagnosed in the U.S each year. As the first and only approved systemic treatment for HCC, Nexavar was a significant step in addressing the unmet need in this field, but effective second-line treatment options are urgently needed for patients", said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "The priority review for regorafenib in the U.S. is great news for patients as it supports our efforts to make this treatment available as early as possible in the second-line setting for HCC in the U.S."

The FDA grants priority review to medicines that if approved, would be significant improvements in the safety or effectiveness of the treatment for serious conditions. Under the Prescription Drug User Fee Act (PDUFA), the FDA aims to complete its review within six months (compared to 10 months under standard review).

Regorafenib is already approved under the brand name Stivarga in many countries, including the U.S., to treat metastatic colorectal cancer and unresectable and/or metastatic gastrointestinal stromal tumors.

The regulatory submission for regorafenib is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] trial. The trial investigated regorafenib in patients with unresectable hepatocellular carcinoma (HCC) whose disease had progressed during treatment with sorafenib (Nexavar) tablets. Results showed that regorafenib significantly improved overall survival (OS) compared to placebo (HR 0.63; 95% CI 0.50-0.79; p<0.001), which over the trial period represents a 37 percent reduction in the risk of death for patients who received regorafenib plus best supportive care (BSC) compared to patients treated with placebo plus BSC. The median OS was 10.6 months in patients treated with regorafenib, compared to 7.8 months in patients who received placebo plus BSC. The safety and tolerability was generally consistent with the known profile of regorafenib, with no clinically meaningful differences in health-related quality of life (HRQoL) between the regorafenib and placebo plus BSC groups. Data from the study were first presented at the 18th World Congress on Gastrointestinal Cancer (WCGC) in June 2016 and published online on December 5, 2016 in the peer-reviewed journal The Lancet.

Regorafenib has also been submitted to regulatory authorities in Japan and the EU for the treatment of second-line HCC and submissions in additional countries are in progress.

About the RESORCE trial
The Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] clinical trial enrolled 573 patients whose disease had progressed during treatment with sorafenib. Patients were randomized in a 2:1 ratio to receive either regorafenib or placebo plus best supportive care.

Patients received 160 mg regorafenib once daily or placebo, for 3 weeks on/1week off, with 28 days constituting one full treatment cycle. The primary endpoint of the study was overall survival, and secondary endpoints were time to progression, progression-free survival, objective tumor response rate and disease control rate. Health-related quality of life was assessed by the FACT-Hep and EQ-5D questionnaires. Safety and tolerability were also continuously monitored.

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. Liver cancer is the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States) and the incidence rate is increasing. In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

Regorafenib is approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU and Japan for the treatment of metastatic colorectal cancer (mCRC). The product is also approved in over 80 countries, including the U.S., countries of the EU and Japan, for the treatment of metastatic gastrointestinal stromal tumors (GIST). In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.