On March 10, 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T-cell immunotherapies for the treatment of cancer, reported the successful recruitment of the planned patients for Phase I of its current clinical trial of dendritic cell (DC) vaccines in acute myeloid leukaemia (AML) (Press release, MediGene, MAR 10, 2016, View Source [SID:1234509481]).

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The independent Data and Safety Monitoring Board (DSMB) recommended advancing the study to Phase II. The DSMB came to a positive evaluation of the obtained safety and tolerability data, after the first six patients were treated with the DC vaccine at least four times.

In the Phase II part of the study, the treatment of the first six patients will continue, and an additional 14 new patients will be recruited. In Phase II, more data will be collected as to the safety profile of the DC vaccines, the induction of tumour-specific immune responses by the vaccine, as well as first signs of efficacy. Medigene’s first company-sponsored DC vaccine trial started at the Oslo University Hospital in March 2015.

Prof. Dolores Schendel, CEO and CSO of Medigene, explains: "We are very pleased that the first part of our study proceeds as scheduled, and we are already preparing the start of Phase II to generate further clinical data on our patients’ response to the treatment. We hope that AML can be better controlled or even eliminated through immune responses induced by our DC vaccines."

Study design: Medigene’s Phase I/II trial (NCT02405338) will include 20 AML patients who show complete remission after standard chemotherapy but are not eligible for stem cell transplantation that would reduce the risk of a relapse. Patients will be vaccinated with Medigene’s DC vaccines for 50 weeks with a follow-up period of one year or until progression of the disease. The primary objective is to prove feasibility and safety of active immunotherapy with Medigene’s dendritic cells. Secondary objectives of the study are induction of tumour-specific immune response, control of minimal residual disease (MRD), and clinical response/time to progression (TTP).

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced of Medigene’s highly innovative and complementary immunotherapy platforms. Currently Medigene evaluates its DC vaccines in a company-sponsored Phase I/II clinical trial in acute myeloid leukaemia (AML). Further studies utilising Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials (IITs), i.e. a clinical Phase I/II trial for the treatment of acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical Phase II trial for prostate cancer treatment at Oslo University Hospital. Moreover, compassionate use[1] patients are treated with DC vaccines at the Department of Cellular Therapy at Oslo University Hospital.

Dendritic cells (DCs) are the most potent antigen-presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognise and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumour cells. The team of Medigene Immunotherapies scientists has developed new, fast and effective methods for generating dendritic cells ex-vivo, which are able to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumour-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or for the use in combination therapies.

Further audio-visual information about Medigene’s DC vaccines at:
View Source

About acute myeloid leukaemia (AML)
Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 incidences are registered annually.
AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a drop in erythrocytes and platelets, for example. Typical symptoms of AML include anaemia, fever, increased risk of infection, and blood coagulation disorder. AML progresses rapidly and may be fatal within a few weeks if untreated.

AML is treated initially with intensive chemotherapy. Another treatment option is allogeneic hematopoietic stem cell transplantation. Unfortunately the majority of patients suffer a relapse. Only about 15 – 20 % of the patients show long-term remission after conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only treatment option that offers a more positive prognosis

On March 10, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that a supplemental Biologics License Application (sBLA) has been submitted to the U.S. Food and Drug Administration (FDA) for the use of ofatumumab (Arzerra) in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) (Press release, Genmab, MAR 10, 2016, View Source [SID:1234509476]). The application was submitted by Novartis under the ofatumumab collaboration between Novartis and Genmab.

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The application is based on results from a Phase III study, COMPLEMENT 2 which evaluated ofatumumab in combination with FC versus FC alone in patients with relapsed CLL. Top-line results from this trial were reported in April 2015. The study met the primary endpoint with a median progression free survival in patients receiving ofatumumab in combination with FC of 28.9 months, compared to 18.8 months in patients receiving FC alone (HR =0.67, p=0.0032).

"The data from the COMPLEMENT 2 study demonstrated the potential of ofatumumab in combination with FC to help patients with relapsed CLL. We are pleased that Novartis has moved forward with a regulatory application for ofatumumab in this indication in the U.S.," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About CLL
CLL is the most common form of leukemia in the western world, accounting for 30% of adult leukemias.1 Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment.2

About COMPLEMENT 2
COMPLEMENT 2 (NCT00824265) is an open-label, two-arm, randomized, Phase III study, which included 365 patients in 18 countries with relapsed CLL. Patients in the study were randomized 1:1 to treatment with up to six cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to six cycles with fludarabine and cyclophosphamide alone.

The primary endpoint of the study was PFS, which was assessed by an Independent Review Committee (IRC) according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines.3 Secondary endpoints included overall response rate, overall survival, patient reported outcomes, time to response, duration of response, time to progression, time to next therapy, safety assessments and quality of life.

About Ofatumumab (Arzerra)
Ofatumumab is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. Arzerra is also approved as extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL in the U.S. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.

Arzerra is not approved anywhere in the world in combination with fludarabine and cyclophosphamide as treatment for relapsed CLL.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Arzerra is marketed under a collaboration agreement between Genmab and Novartis. Novartis has rights to develop ofatumumab in autoimmune indications, including multiple sclerosis.

On March 10, 2016 Trillium Therapeutics Inc. (Nasdaq:TRIL; TSX: TR) a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported that it has entered into a collaboration agreement with University Health Network and the Hospital for Sick Children to fund and undertake a research program entitled "SIRPaFc: Translating Genomics Research Into a Novel Cancer Immunotherapy (Filing, 6-K, Trillium Therapeutics, MAR 10, 2016, View Source [SID:1234509472]).

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" Importantly, this project has been approved for funding by Genome Canada under the Genomic Applications Partnership Program (GAPP). In addition, The Ontario Ministry of Research and Innovation is supporting the project with a grant matching Genome Canada’s contribution, providing the collaboration with 3-year budget of approximately $3.4 million.

"Predictive prognostic or pharmacodynamic biomarkers are critical for the development of new therapeutic cancer agents, especially those targeting the immune system," commented Trillium’s Chief Executive Officer, Dr. Niclas Stiernholm. "This new matching funding will allow us to substantially expand our translational research efforts, focusing primarily on acute myeloid leukemia, which is ultimately likely to enhance our clinical programs."

Trillium’s lead program, TTI-621, is currently being tested as a single-agent in patients with relapsed or refractory hematologic malignancies. During the dose escalation phase set to enroll up to 36 subjects, we intend to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics to determine the optimal dose for subsequent enrollment in the expansion phase. In this second part of the trial, we intend to explore the safety and preliminary antitumor activity of TTI-621 at the optimal dose identified in the escalation phase in 12–15 subjects per hematologic malignancy type: indolent B-cell lymphoma, aggressive B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome.

On March 10, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported the publication of an article evaluating the therapeutic potential of YELIVA (ABC294640), the Company’s orally-administered first-in-class Sphingosine kinase-2 (SK2) selective inhibitor, in the treatment of cholangiocarcinoma (bile duct cancer) (Press release, RedHill Biopharma, MAR 10, 2016, View Source [SID:1234509463]).

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The article, authored by scientists from the Mayo Clinic Cancer Center, the Hollings Cancer Center at the Medical University of South Carolina and Apogee Biotechnology Corporation ("Apogee"), will be published in Oncotarget and is available online on the journal’s website.

The article[1], entitled "Antitumor effect of the novel sphingosine kinase-2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells," found that SK2 is overexpressed in multiple human cholangiocarcinoma cell lines, including a patient-derived line. The article describes non-clinical studies conducted with YELIVA (ABC294640) in these cell lines. The results from these studies demonstrated that YELIVA inhibited cancer proliferation and induced apoptosis in these cholangiocarcinoma cancer cells. Furthermore, YELIVA inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cell proliferation and survival, and also induced autophagy. In addition, YELIVA in combination with sorafenib, an FDA-approved multikinase inhibitor for the treatment of hepatocellular carcinoma and renal cell carcinoma (NEXAVAR marketed by Bayer AG), synergistically inhibited the proliferation of cholangiocarcinoma cells.

The authors concluded that these findings provide preliminary insight into the possible use of YELIVA as an anticancer drug for cholangiocarcinoma treatment, as well as novel evidence that SK2 may be a rational therapeutic target in the treatment of this cancer. Additionally, a combination of YELIVA with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.

Reza Fathi, RedHill’s Senior VP R&D, said: "We are pleased to announce the publication of this important article in a well-respected, peer-reviewed journal. The findings described in this publication provide further insight into the mechanism of the anticancer activities of YELIVA, a novel Sphingosine kinase-2 (SK2) inhibitor, and suggest that YELIVA could potentially be effective in treating cholangiocarcinoma cancer. Notably, it was found that YELIVA inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. We continue to diligently advance the clinical research of YELIVA for multiple indications. We have initiated a Phase I/II study with YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma and plan to initiate two additional Phase II studies, for multiple myeloma and radioprotection, during 2016. We are planning additional clinical programs with this novel and promising drug candidate for oncology, inflammatory and gastrointestinal indications."

Charles D. Smith, Ph.D., Apogee’s President and CEO and a co-author of the article, added: "We are pleased that these results provide a rationale for use of YELIVA in a very difficult to treat malignancy. These results further add to the breadth and importance of YELIVA’s mechanism of action studies in multiple human tumors."

Cholangiocarcinoma is a rare cancer that develops in the bile ducts, characterized by its late diagnosis and high mortality rates. Cholangiocarcinoma is the second most common primary liver tumor, accounting for approximately 10-15% of all hepatobiliary malignancies[2]. Although a rare cancer, the incidence and mortality rates of cholangiocarcinoma have been increasing worldwide in the last three decades. The five year survival rates following diagnosis have not increased during this time period, and remain at 10%[3]. Surgery is the only curative treatment option, but only for the minority of patients diagnosed with early-stage disease.

RedHill announced in October 2015 positive top-line results from a Phase I study with YELIVA in patients with advanced solid tumors, the majority of which were gastrointestinal cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers. Top-line results demonstrated that YELIVA can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity, based on levels required in preclinical models. The study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA resulted in a rapid and pronounced decrease in S1P levels over the first 12 hours, with return to baseline at 24 hours, which is consistent with clearance of the drug, with several patients having prolonged stabilization of disease.

A Phase I/II clinical study was initiated in the U.S. evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), including in patients with HIV-related DLBCL. The study is being conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans and is supported by a grant awarded to Apogee from the NCI Small Business Technology Transfer (STTR) program, as well as additional support from RedHill. The Phase I/II clinical study in patients with refractory/relapsed diffuse large B-cell lymphoma and the Phase I clinical study in cancer patients with advanced solid tumors are registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies.

A Phase I/II study with YELIVA for the treatment of refractory or relapsed multiple myeloma is planned to be initiated in the second quarter of 2016. The study will be conducted at Duke University Medical Center. The study is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee in conjunction with Duke University, with additional support from RedHill.

A Phase II clinical study to evaluate YELIVA as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the U.S. during the second half of 2016, subject to regulatory and other conditions.

_______________________
[1] The article was authored by Xiwei Ding, Roongruedee Chaiteerakij, Catherine D. Moser, Hassan Shaleh, Jeffrey Boakye, Gang Chen, Albert Ndzengue, Ying Li, Yanling Zhou, Shengbing Huang, Frank A. Sinicrope, Xiaoping Zou, Melanie B. Thomas, Charles D. Smith, Lewis R. Roberts
[2] A. Bergquist et al. Epidemiology of cholangiocarcinoma, Best Pract Res Clin Gastroenterol. 2015 Apr;29(2):221-32
[3] S. Rizvi and G. J. Gores, Pathogenesis, diagnosis, and management of cholangiocarcinoma, Gastroenterology, vol. 145, no. 6, pp. 1215-1229, 2013.

About YELIVA (ABC294640):

YELIVA (ABC294640) is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. A Phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. The development of YELIVA was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development.

On March 10, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the selection of a recommended Phase 2 dose (RP2D) and initiation of the Phase 1b portion of its Phase 1/1b clinical trial of RXDX-105, the company’s orally available, small molecule multikinase inhibitor with potent activity against such targets as RET and BRAF (Press release, Ignyta, MAR 10, 2016, View Source [SID:1234509455]). The Phase 1b portion of the study utilizes a basket design focusing on patients with solid tumors that contain molecular alterations of RET or BRAF.

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"We are excited to embark on further clinical evaluation of RXDX-105 in selected, molecularly-defined patient populations through this Phase 1b clinical trial expansion," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "In the now-completed Phase 1 dose escalation and dose finding portion of this clinical study, patients were enrolled without selection for molecular alterations. Given the performance of RXDX-105 in that setting, we now look forward to evaluating this investigational agent at the RP2D in targeted patient populations. We also look forward to providing a clinical data update on this program at an upcoming scientific conference."

About RXDX-105

RXDX-105 is an orally available, small molecule multikinase inhibitor with potent activity against such targets as RET and BRAF.

In November 2015, Ignyta announced interim results from the Phase 1 clinical trial of RXDX-105, which were presented at the 27th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts.

The dose escalation clinical trial was designed to determine the maximum tolerated dose (MTD) and/or RP2D, as well as preliminary anti-cancer activity, of single agent RXDX-105 in patients with advanced or metastatic solid tumors that were not selected based on any molecular alteration.

As of the October 26, 2015, data cut-off for the presentation, the findings showed:

A total of 41 patients with a range of solid tumors were dosed in the clinical trial;
RXDX-105 was well-tolerated;
The MTD and RP2D had not yet been determined;
Pharmacokinetic measurements showed increased exposure with increasing dose, with a half-life compatible with once-daily dosing. Dosing in the fed state appears to further increase exposure;
Exposure was reaching levels expected to be efficacious based on tumor growth inhibition in animal models of RET- and BRAF-driven tumors; and
Tumor regression was observed in six patients treated with 275 mg, including one confirmed partial response (40% reduction) in a patient with non-small cell lung cancer with a KRAS G12C mutation. Two additional patients with thyroid cancer and squamous cell lung cancer exhibited reductions of 20% and 27%, respectively. In patients with tumor regression, there appears to be an exposure/response correlation.

About Ignyta, Inc.

At Ignyta, we fight cancer – a formidable opponent that manifests as thousands of different molecularly defined diseases and takes away millions of lives globally, every year. In this fight, our big hairy audacious goal (BHAG) is not just to shrink tumors but to eradicate residual disease – the source of cancer relapse and recurrence – in precisely defined patient populations by 2030. We will work tirelessly to achieve this BHAG by pursuing an integrated therapeutic (Rx) and companion diagnostic (Dx) strategy for treating cancer patients. Our Rx efforts are focused on discovering, in-licensing or acquiring, then developing and commercializing, molecularly targeted therapies that, sequentially or in combination, are foundational for eradicating residual disease. Our Dx efforts aim to pair these product candidates with biomarker-based companion diagnostics that are designed to precisely identify, at the molecular level, the patients who are most likely to benefit from the therapies we develop. We believe that only through this integrated Rx/Dx approach can we succeed in this fight. For more information, please visit: www.ignyta.com.