On January 8, 2020 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported that the first patient has been dosed in the Phase III GEMSTONE-304 study of the Company’s anti-PD-L1 antibody CS1001 in combination therapy as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC) (Press release, CStone Pharmaceauticals, JAN 8, 2020, View Source [SID1234552811]). The GEMSTONE-304 trial is a multicenter clinical study designed to evaluate the efficacy and safety of CS1001 in combination with 5-fluorouracil plus cisplatin (FP) doublet chemotherapy in the first-line treatment of unresectable locally advanced, relapsed, or metastatic ESCC.

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According to the GLOBOCAN data released in 2018, there are approximately 307,000 new incidences of esophageal cancer and 283,000 cases of esophageal cancer-related deaths in China annually. The incidence and mortality rates of esophageal cancer are ranked 5th and 4th respectively among all tumor types nationwide. Epidemiological data indicate that 90% of all esophageal cancer cases in China are ESCC, and around 70% of ESCC cases were locally advanced or metastatic at the time of diagnosis. The platinum-based doublet chemotherapy is the current standard of care first-line treatment for patients with advanced ESCC, but it has limited efficacy. Existing data on this first-line treatment for advanced ESCC suggest an objective response rate (ORR) of 35%, a median progression-free survival (PFS) of less than six months, and a median overall survival (OS) of less than one year. There are no alternative treatments for ESCC patients who have failed the first-line treatment.

CS1001 is an investigational anti-PD-L1 antibody developed by CStone. Results released at the 2019 Chinese Society of Clinical Oncology (CSCO) Annual Meeting have shown that, as of July 1, 2019, the Phase Ib trial of CS1001 in combination with the FP chemotherapy regimen in first-line treatment of ESCC achieved an ORR of 77.8% with durable response as well as good overall safety and tolerability.

"Esophageal cancer is one of the tumor types that are particularly prevalent in China, with over 50% of the world’s new esophageal cancer cases and related deaths occurring in the country. Furthermore, the lack of more effective treatments for this patient population has long represented an urgent unmet clinical need," said Dr. Frank Jiang, Chairman and CEO of CStone. "I am glad that we have dosed the first patient in the GEMSTONE-304 trial. I hope CS1001 will continue to demonstrate its clinical promise in its development programs, and soon be proven as a new treatment option for ESCC patients in China."

"Early symptoms of esophageal cancer are relatively silent; as a result, esophageal cancer patients are commonly diagnosed at advanced stages for which there are very limited treatment options. Furthermore, no immunotherapy has been approved for the first-line treatment of ESCC. Recent results from the Phase Ib trial of CS1001 have already demonstrated promising preliminary antitumor efficacy in advanced ESCC. We will continue accelerate this Phase III trial with our best effort. Should this clinical program lead to successful outcomes, it will be a major breakthrough for advanced ESCC patients who are in urgent need of effective therapies," noted Dr. Jason Yang, Chief Medical Officer of CStone.

About CS1001

CS1001 is an investigational monoclonal antibody directed against PD-L1 being developed by CStone. Authorized by the U.S. based Ligand Corporation, CS1001 is developed by the OMT transgenic animal platform, which can generate fully human antibodies in one step. As a fully human, full-length anti-PD-L1 monoclonal antibody, CS1001 mirrors natural G-type immune globulin 4 (IgG4) human antibody, which can reduce the risk of immunogenicity and potential toxicities in patients, potentially representing a unique advantage over similar drugs.

CS1001 has completed a Phase 1 dose-escalation study in China, in which the drug showed good tolerability. During Phase 1a and 1b stages of the study, CS1001 produced sustained clinical benefits in multiple tumor types.

CS1001 is being investigated in a number of ongoing clinical trials, including one Phase 1 bridging study in the U.S. In China, its clinical program includes one multi-arm Phase 1b study, two pivotal Phase 2 studies, and four Phase 3 studies for several tumor types.

On January 7, 2020 Theolytics, a UK biotech harnessing viruses to combat cancer, reported the closing of a US $6.8 million (UK £5 million) Series A round (Press release, Theolytics, JAN 7, 2020, View Source [SID1234630929]). The round was co-led by Epidarex Capital and Taiho Ventures LLC with participation from existing investor, Oxford Sciences Innovation (OSI). The financing will be used to progress the company’s pipeline of candidates towards human clinical trials.

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Theolytics is focused on creating a step-change in the oncolytic viral therapy field, by using its phenotypic screening platform to discover and develop highly efficacious, targeted candidates, suitable for intravenous delivery and optimised for a chosen cancer patient population.

Charlotte Casebourne, CEO of Theolytics said, "Oncolytic viruses represent a unique therapeutic paradigm within oncology. Theolytics’ platform technology enables a fundamental shift in what is possible; combining the power of bioselection with a patient-centric approach to drug discovery, we are able to address many of the challenges that have prevented the field from delivering on its full potential. Our team are committed to discovering and developing candidates for some of the most challenging cancers, and I’m delighted that Epidarex and Taiho Ventures have chosen to support us on our journey."

Henning Steinhagen, Venture Partner at Epidarex Capital said, "The oncolytic viral therapy field continues to gain momentum and Theolytics caught our eye with their highly promising indication-specific bioselection platform. Theolytics combines multiple key features we are looking for when investing: world class science, highly driven innovators, and a disruptive technology that has the potential to generate a strong pipeline of proprietary and significantly more efficacious therapeutics. We look forward to supporting Theolytics in leveraging its innovative platform to establish a pipeline of patient-centric next-generation oncolytic viruses, which promises to dramatically improve the treatment of cancer."

Sakae Asanuma, President at Taiho Ventures, LLC, the corporate venture arm of Taiho Pharmaceutical Co. Ltd., said, "Taiho is delighted to co-lead this Series A financing and work with Theolytics to deliver the innovative oncolytic virotherapy generated by their unique proprietary platform technology, which should provide cancer patients with the promise of dramatically improving clinical outcomes."

Dr Kenneth Powell, Chair of the Board welcomed Henning Steinhagen, Venture Partner at Epidarex, and Sakae Asanuma, President at Taiho Ventures as new Board members, stating, "I look forward to working with our new investors to bring these promising approaches to cancer patients."

On January 7, 2020 Sanford Burnham Prebys Medical Discovery Institute reported that identified a new way to boost the immune system’s ability to fight cancer (Press release, Sanford-Burnham Medical Research Institute, JAN 7, 2020, View Source [SID1234553267]). The study, which was performed in collaboration with NYU Langone’s Perlmutter Cancer Center, used a mouse model to identify the importance of the Siah2 protein in the control of immune cells called T regulatory cells (Tregs), which limit the effectiveness of currently used immunotherapies. The research, which offers a new avenue to pursue immunotherapy in cases where the treatment fails, was published today in Nature Communications.

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"While Siah2 is involved in control of activities that govern cancer development, this study offers the first direct evidence for its role in the immune system, namely in anti-tumor immunity," says Ze’ev Ronai, Ph.D., professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program and senior author of the study. "Our study shows that a PD-1 inhibitor can be used to treat tumors that currently do not respond to this therapy, when administered in mice lacking the Siah2 gene, thereby offering a means to expand the effectiveness of immunotherapy. The findings also provide further justification for our efforts to find a drug that blocks Siah2."

The development of cancer immunotherapies, which harness the power of an individual’s immune system to destroy tumors, has revolutionized the treatment of certain cancers. For some people with advanced melanoma, a deadly skin cancer, the treatment has extended survival to years instead of months. However, the treatment only works for about 40% of people with advanced melanoma. The study from the Ronai lab offers a new means to make this treatment effective in individuals who at present do not respond to anti-PD-1 therapy.

Ronai explains, "In our study, mice lacking the Siah2 gene were able to mount an immune attack against melanoma. Moreover, the effectiveness of Siah2 in immunotherapy was demonstrated for ‘cold’ tumors—those that do not respond to immunotherapy—which were effectively eliminated by a PD-1 blockade in Siah2-mutant mice."

"Understanding the basic mechanisms of tumor immunity will ultimately help us improve the effectiveness of immunotherapy," says Michael Rape, Ph.D., Howard Hughes Investigator and professor of Cell and Developmental Biology at University of California, Berkeley. "This study uncovers an important layer in the regulation of key immune cell components that impact the effectiveness of cancer immunotherapy, highlighting the need to develop inhibitors for Tregs, in which a Siah2 inhibitor holds promise."

Scientists have known for many years that Siah2 is involved in cellular responses to hypoxia (low oxygen) and the unfolded protein response—two processes that are exploited by tumors to keep growing. Ronai has studied the protein for nearly a decade in hopes of finding better cancer treatments: His team is currently working to develop a small molecule drug that blocks the protein. Now, Ronai’s study shows that the protein also plays an important role in regulating the immune system’s response to a tumor.

In the study, the scientists used genetically engineered mice that did not produce the Siah2 protein and then introduced BRAF-mutant melanoma—a mutation that occurs in about half of human melanomas. This approach allowed the researchers to study the role of Siah2 in the tumor’s microenvironment, of which the immune system is a major component. In the absence of the Siah2 gene, the melanoma tumors receded—a stark contrast to mice with the Siah2 gene, in which the tumor continued to grow. Giving these mice anti-PD-1 therapy effectively eliminated melanoma that otherwise resisted this therapy, demonstrating a new path to enhance the effectiveness of current immunotherapies.

Digging deeper into their findings, the scientists discovered that in the Siah2 mutant mice, the tumors were infiltrated by killer but not Treg immune cells—indicating the immune system was more active in clearing the tumors. The lack of the Treg cells was attributed to reduced proliferation and recruitment into the tumor due to the role of Siah2 and its control of cell cycle regulatory proteins.

"Our discovery only fuels our sense of urgency to find a drug that inhibits Siah2," says Ronai. "Using an arsenal of novel approaches should enable us to advance the targeting of Siah2 in both the tumors and their microenvironment."

The first author of the study is Marzia Scortegagna, Ph.D., of Sanford Burnham Prebys. Additional study authors include Yongmei Feng, Ph.D., Dennis C. Otero, Ph.D., Linda M. Bradley, Ph.D., and Yan Li, M.D., Ph.D., of Sanford Burnham Prebys; Kathryn Hockemeyer, M.D., Ph.D., Igor Dolgalev and Ioannis Aifantis, Ph.D., of NYU School of Medicine; Joanna Poźniak, Ph.D., Florian Rambow, Ph.D., and Jean-Christophe Marine, Ph.D., of VIB; Roberto Tinoco, Ph.D., of Sanford Burnham Prebys and the University of California, Irvine; Tongwu Zhang, Ph.D., and Kevin Brown, Ph.D., of the National Cancer Institute; and Marcus Bosenberg, M.D., Ph.D., of Yale School of Medicine.

On January 7, 2020 Leap Therapeutics, Inc. (Nasdaq: LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported the closing of its previously announced equity financing to issue 1,421,801 shares of newly designated Series A mandatorily convertible preferred stock to a lead institutional investor, at a price of $10.54 per share, and an aggregate of 1,137,442 shares of newly designated Series B mandatorily convertible preferred stock to BeiGene and Perceptive Advisors, at a price of $10.55 per share (Press release, Leap Therapeutics, JAN 7, 2020, View Source [SID1234553263]). The preferred stock price reflects a common stock equivalent price of $1.055 per share, the closing price for Leap’s common stock on the Nasdaq Global Market on the day of pricing, January 2, 2020 and, in the case of the Series A mandatorily convertible preferred stock, reflects a per share reduction equal to the exercise price of the pre-funded warrant issued upon conversion of the Series A mandatorily convertible preferred stock. The holder of Series A mandatorily convertible preferred stock also received a share of a newly designated special voting preferred stock that will entitle it to elect one member of Leap’s Board of Directors.

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Upon approval by the stockholders of Leap, the Series A mandatorily convertible preferred stock will automatically convert into pre-funded warrants to purchase 14,218,010 shares of common stock and the Series B mandatorily convertible preferred stock will automatically convert into 11,374,420 shares of common stock, plus that number of additional shares of common stock representing payment of an 8% per annum accruing dividend on each share of preferred stock as of the conversion date. Upon stockholder approval and conversion of the preferred stock, the investors will also receive warrants to purchase up to an equal number of shares of common stock at an exercise price of $2.11 per share. The aggregate gross proceeds to Leap from this offering are approximately $27 million, before deducting placement agent fees and estimated offering expenses payable by Leap, and excluding proceeds from the exercise of any warrants.

Raymond James & Associates, Inc. was the placement agent for the equity financing.

The securities sold in the private placement have not been registered under the Securities Act of 1933, as amended, or state securities laws and may not be offered or sold in the United States absent registration with the Securities and Exchange Commission (SEC) or an applicable exemption from such registration requirements. Leap has agreed to file a registration statement with the SEC covering the resale of the shares of common stock issuable upon conversion of the preferred stock and exercise of the warrants issued in the private placement.

This press release does not constitute an offer to sell or the solicitation of an offer to buy the securities, nor shall there be any sale of the securities in any state in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state.

On January 7, 2020 ECOG-ACRIN reported that the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has promising activity in HER2 amplified salivary gland tumors, according to data published in the Annals of Oncology (Press release, ECOG-ACRIN, JAN 7, 2020, View Source [SID1234553261]). The publication is for ‘Arm Q,’ which is one of nearly 40 single-arm phase two treatments in the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) trial. NCI-MATCH is being co-led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and the National Cancer Institute (NCI), part of the National Institutes of Health.

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"We saw that two of the three NCI-MATCH patients with salivary gland tumors had significant tumor shrinkage by at least 30% with T-DM1 treatment, and this benefit lasted," said lead researcher Komal Jhaveri, MD, FACP, a medical oncologist and early-phase clinical trials specialist at Memorial Sloan Kettering Cancer Center in New York. "The benefit lasted two years in the patient with squamous cell cancer of the parotid gland, and nine months in the case of mucoepidermoid carcinoma of the parotid gland."

"This is a hint of activity that needs to become the focus of a larger trial," said Dr. Jhaveri.

Another recent T-DM1 trial (not part of the NCI-MATCH trial) reported interim results at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). In that trial (NCT02675829), nine of the 10 patients with salivary gland cancers treated with T-DM1 responded either with tumor shrinkage by computed tomography (CT) scan or as assessed by positron emission tomography (PET). As a result, that trial has since been expanded to enroll additional patients.

T-DM1 is a targeted therapy that contains the monoclonal antibody trastuzumab, which binds to the HER2 protein found on some cancer cells. It also contains the cytotoxic drug DM1, which inhibits tumor cell division. Unlike chemotherapy, antibody-drug conjugates like T-DM1 are intended to target and kill tumor cells while sparing healthy cells. T-DM1 has improved overall survival and led to a new standard of care in HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane.

The primary objective of each arm in NCI-MATCH is to estimate the proportion of patients who had an objective response (OR). Under predefined criteria, an OR rate greater than 16% in a given NCI-MATCH arm would warrant further study of the agent(s).

Although the results from Arm Q did not meet these criteria, the signal in salivary gland tumors is important.

"We are excited about the prospect of this and other upcoming MATCH arms to shed new light on responsive tumor types, as there is far less data available in rare and uncommon disease types from previously conducted trials," said Keith T. Flaherty, MD, a medical oncologist at Massachusetts General Hospital Cancer Center in Boston and ECOG-ACRIN study chair for the overall NCI-MATCH trial. "Salivary cancer is a particularly understudied area and seeing evidence of benefit for a molecularly targeted approach strongly supports further focus on this cancer type."

Patients received T-DM1 at 3.6 mg/kg intravenously every three weeks until toxicity or disease progression.

Of the 38 patients enrolled in Arm Q, 36 were included in the efficacy analysis. Overall, this was a heavily pretreated group of patients with multiple unique histologies (excluding breast and gastric). Seventeen patients (47%) had stable disease with median duration of 4.6 months, including eight of 10 patients with ovarian and uterine carcinomas. The six-month progression-free survival rate was 23.6%. Common toxicities were fatigue, anemia, fever and thrombocytopenia. However, this arm did not find any new toxicities for T-DM1.

There was a trend for tumor shrinkage with higher levels of gene copy number as determined by the tumor sequencing assay. The median HER2 copy number was 17 (range: seven-139). Notably, the patient with squamous cell cancer of the parotid gland had a HER2 gene copy number of 129 and the patient with mucoepidermoid carcinoma of the parotid gland had a copy number of 21.

"NCI-MATCH seeks to determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of their cancer type," said Lyndsay Harris, MD, Associate Director, Cancer Diagnosis Program, NCI, and co-PI of the NCI-MATCH trial. "In certain studies, such as this, we also saw benefit in rare tumor types. Such discoveries could be eligible to move on to larger, more definitive trials."

The publication (Annals of Oncology, Volume 30, Issue 11, November 2019) marks a milestone for the NCI-MATCH trial, being the first results manuscript to appear in print. The manuscript was previously published online ahead of print (View Source).

Genentech Inc. provided ado-trastuzumab emtansine for Arm Q under a Clinical Trial Participation Agreement between NCI and Genentech.

NCI-MATCH treatment arms are posted at View Source