On January 4, 2017 CytRx Corporation (NASDAQ: CYTR), a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing new therapeutics to treat patients with cancer, reported that, in response to a request from the company, the U.S. Food and Drug Administration (FDA) has agreed to a Type B pre-NDA meeting at which the company will seek input on its planned New Drug Application (NDA) for aldoxorubicin as a new second-line treatment for patients with soft tissue sarcomas (STS) (Press release, CytRx, JAN 4, 2017, View Source [SID1234517261]). Assuming a positive outcome from this pre-NDA meeting, CytRx expects to submit an NDA for aldoxorubicin to the FDA in the last quarter of 2017, and, subject to FDA approval, bring aldoxorubicin to market next year.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Based on positive, statistically significant results from our pivotal Phase 3 trial evaluating aldoxorubicin compared to investigator’s choice in patients with previously treated relapsed or refractory sarcomas, we requested, and were recently granted, a Type B meeting with the FDA," said Daniel Levitt, M.D., Ph.D., Chief Operating Officer and Chief Medical Officer of CytRx. "The purpose of this meeting is to share the Phase 3 data with the Agency and discuss the regulatory path forward for aldoxorubicin. In our view, this meeting is an important next step toward our goal of bringing aldoxorubicin to the thousands of patients in need of a new treatment for relapsed soft tissue sarcoma."

Overview of the Updated Phase 3 Trial and Results

The randomized, controlled Phase 3 trial enrolled a total of 433 patients at 79 clinical sites. Patients with metastatic, locally advanced or unresectable soft tissue sarcomas who had either not responded to, or who had progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapy were randomized 1:1 to be treated with aldoxorubicin or the investigator’s choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide, dacarbazine, pazopanib (Votrient), or gemcitabine plus docetaxel. The primary endpoint of the study is PFS. Secondary endpoints include overall survival, response rates, disease control rates and safety.

In November 2016, CytRx reported positive results which demonstrated a statistically significant improvement in progression-free survival (PFS) between aldoxorubicin and investigator’s choice therapy in 246 patients with leiomyosarcoma and liposarcoma, (p=0.007). The hazard ratio (HR) was 0.62 (95% CI 0.44-0.88), representing a 38% reduction in the risk of tumor progression for patients receiving aldoxorubicin versus investigator’s choice. Leiomyosarcoma and liposarcoma are the two most common types of STS and accounted for 57% of the patients enrolled in the trial. Aldoxorubicin also demonstrated a statistically significant improvement in PFS over investigator’s choice in 312 patients treated in North America (p=0.028; HR=0.71, 95% CI 0.53-0.97). Notably, aldoxorubicin performed better than investigator’s choice for the entire study population and narrowly missed statistical significance (p=0.12; HR=0.81, 95% CI 0.64-1.06). All responses were determined by an independent, blinded central lab assessment of scans.

Aldoxorubicin did not cause clinically significant cardiac, renal, or hepatic toxicities. For the global trial population, the most commonly reported adverse events were neutropenia and anemia consistent with prior clinical trials with aldoxorubicin. Grade 3 or higher adverse events were manageable with supportive care and occurred at a rate of 61% for patients receiving aldoxorubicin and 46% in patients treated with investigator’s choice. Importantly, treatment-emergent adverse events leading to discontinuation occurred in 4.2% of patients treated with aldoxorubicin, compared to 6.3% for patients receiving investigator’s choice.

Patients continue to be followed for overall survival (OS), a secondary endpoint, and CytRx expects the OS data to be available in 2017.

About Soft Tissue Sarcoma

Soft tissue sarcoma is a cancer occurring in muscle, fat, blood vessels, tendons, fibrous tissues and connective tissue. It can arise anywhere in the body at any age. STS remains a high unmet medical need because of the difficulty in treating the more than 50 types of this aggressive cancer. According to the American Cancer Society, in 2016 more than 12,300 new cases were diagnosed in the U.S. and approximately 5,000 Americans died from this disease. In addition, approximately 40,000 new cases and 13,000 deaths in the U.S. and Europe are part of a growing underserved market.

About Aldoxorubicin

Aldoxorubicin is a rationally-engineered cytotoxic which combines doxorubicin, a widely used chemotherapeutic agent, with a novel linker molecule that binds directly and specifically to circulating albumin, the most abundant protein in the bloodstream. Protein-hungry tumors concentrate albumin, which facilitates the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. Typically, doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Using this acid-sensitive linker technology, aldoxorubicin delivers greater doses of doxorubicin (3 ½ to 4 times). To date, there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 6,500 mg/m2 of doxorubicin equivalents. Aldoxorubicin is the first-ever single agent to show superiority over doxorubicin in a randomized clinical trial in first-line STS.

On January 4, 2017 OncoMed Pharmaceuticals, Inc. (NASDAQ:OMED), a clinical-stage company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported dosing of the first patient in a Phase 1b clinical trial of anti-DLL4/VEGF bispecific antibody (OMP-305B83) plus chemotherapy in patients with second-line metastatic colorectal cancer (Press release, OncoMed, JAN 4, 2017, View Source [SID1234517259]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The anti-DLL4/VEGF is the first antibody developed utilizing OncoMed’s BiMAb bispecific platform technology and is designed to have anti-cancer stem cell, immunomodulatory and anti-angiogenic activity. Thirty patients with metastatic colorectal cancer who have failed first-line treatment, typically bevicizumab plus FOLFOX (folinic acid, fluorouracil, oxaliplatin) chemotherapy, will receive second-line treatment in the Phase 1b multicenter, open-label dose escalation and expansion study of the anti-DLL4/VEGF bispecific antibody in combination with FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy. This trial is designed to determine the safety, preliminary efficacy, immunogenicity, pharmacokinetics and biomarker effects of the anti-DLL4/VEGF bispecific antibody plus FOLFIRI. A second Phase 1b study in patients with platinum resistant ovarian cancer is expected to begin enrolling patients soon.

"Metastatic colorectal cancer is an indication that we believe may benefit from the combined inhibition of DLL4 and VEGF plus chemotherapy," said Robert Stagg, Pharm.D., OncoMed’s Vice President, Clinical Research. "Anti-VEGF therapy plus 5-fluorouracil-based chemotherapy is currently approved in the treatment of second-line metastatic colorectal cancer, and this Phase 1b clinical trial is an opportunity to study the safety and preliminary efficacy of our anti-DLL4/VEGF bispecific antibody in combination with 5-fluorouracil-based chemotherapy and to observe if the multi-pronged mechanism of action may provide signs of enhanced activity."

In an ongoing Phase 1a dose escalation and expansion study of OncoMed’s anti-DLL4/VEGF bispecific antibody as a single agent, interim data was presented on 51 patients with previously treated advanced solid tumors who were treated in the dose escalation portion of the trial. Additional patients are currently being enrolled in the expansion phase of the study. Anti-DLL4/VEGF bispecific antibody was generally well tolerated with hypertension, headache and pulmonary hypertension being the most common drug related toxicities. Single-agent anti-tumor activity was observed: two of 46 evaluable patients had a partial response and 12 other patients had a reduction in their tumor volume. One of the two colorectal patients on study had a reduction in tumor volume.1

About anti-DLL4/VEGF Bispecific Antibody (OMP-305B83)
OncoMed’s anti-DLL4/VEGF bispecific antibody is designed to inhibit the function of both DLL4 and VEGF and thereby induce potent anti-tumor responses while mitigating certain angiogenic-related toxicities. It was developed utilizing OncoMed’s BiMAb bispecific platform technology, which enables the design of bispecific antibodies comparable to traditional monoclonal antibodies but possessing dual target-binding specificity.

In preclinical studies OncoMed’s anti-DLL4/VEGF bispecific antibody demonstrated robust in vivo anti-tumor efficacy across a range of solid tumor xenografts, including colon, ovarian, lung and pancreatic cancers, among others. Further, in preclinical studies dual inhibition of DLL4 and VEGF appears to exhibit synergistic anti-tumor activity at doses where blockade of either target alone elicited sub-optimal activity.

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.