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Celyad’s NKR-2 Phase I safety trial delivers encouraging results to be presented at ASH 2016

On November 7, 2016 Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, reported that first data analysis of the NKR-2 Phase I trial shows encouraging results which will be presented during a poster session at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place on December 3-6, 2016, in San Diego, CA (Press release, Celyad, NOV 7, 2016, View Source [SID1234516387]).

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The NKR-2 Phase I trial is a single infusion, dose escalation study evaluating the safety and feasibility of NKR-2 T-cells in Acute Myeloid Leukemia and Multiple Myeloma patients. This study was completed in September 2016 with a successful safety follow-up for all dose level cohorts. There were no cases of cytokine release syndrome, cell-related neurotoxicity, auto-immunity, or CAR-T related death.

Based on recent analysis, encouraging clinical update and correlative analysis, including post-infusion immunophenotyping, will be presented at the poster session of the ASH (Free ASH Whitepaper) Annual Meeting:

Title: Safety Data from a First-in-Human Phase 1 Trial of NKG2D Chimeric Antigen Receptor-T Cells in AML/MDS and Multiple Myeloma (Poster Presentation)
Abstract: 4052
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Presentation: Monday, December 5, 2016, 6:00pm – 8:00pm PST
Location: San Diego Convention Center, Hall GH
Dr. Christian Homsy, CEO of Celyad commented: "NKR-2 Phase I trial was a safety study with the primary objective of ensuring that there was no on-target, off-tumor toxicity. We are positively surprised at reports of unexpected clinical benefit, while testing just one single infusion dosed between 50 and 1,000 times lower than our expected efficacious dose extrapolated from animal experiments. Our exceptionally strong animal data was obtained with three injections of human equivalent doses of 1 to 2 billion cells per injection, while the highest dose tested in the NKR-2 study was 30 million cells in a single infusion. These results are therefore encouraging and we look forward to triggering the next phase of our NKR-T program once European agencies and the FDA have approved our THINK trial protocol".

Dr. Frédéric Lehmann, VP Immuno-Oncology at Celyad: "We are excited to present these data at ASH (Free ASH Whitepaper) and to explore the full potential of our NKR-2 autologous therapy in our next development phase. The THINK trial will evaluate the clinical activity and safety in seven indications, in both hematologic malignancies and solid tumors. It is our hope that this study will be the foundation of a robust approach to treating patients with advanced tumors."

Dr. David Gilham, VP Research and Development at Celyad: "NKR-2 CAR T cell therapy was designed to act like a drug with short term persistence and multiple injections in order to provide a better controlled and more predictable safety profile than that of other traditional CAR-T products. The primary objective is to avoid uncontrolled in-vivo cell expansion and long term persistence thereby replacing this paradigm with well controlled pharmacokinetics. We are re-assured to note that the safety outcome of this Phase I study confirms the pre-clinical animal data generated to date."

Preclinical Data Published in PLOS ONE Support Use of a Patient Selection Biomarker for Biothera Pharmaceuticals’ Phase 2 Cancer Immunotherapy Imprime PGG

On November 7, 2016 Biothera Pharmaceuticals, Inc. reported the publication of preclinical research identifying an essential mechanism in the activation of anti-cancer immune responses by Imprime PGG, the Company’s Phase 2 cancer immunotherapy drug (Press release, Biothera, NOV 7, 2016, View Source [SID1234516380]). The formation of an immune complex between Imprime PGG and endogenous anti-beta glucan antibodies (ABA) offers the potential to use a biomarker for selecting patients most likely to respond to Imprime-based therapy. The results were published recently in PLOS ONE, a peer-reviewed open access scientific journal, in an article titled, "Imprime PGG-mediated Anti-cancer Immune Activation Requires Immune Complex Formation."

Imprime PGG acts as a Pathogen Associated Molecular Pattern (PAMP) that activates the innate immune system to enhance the efficacy of immune checkpoint inhibitors, as well as tumor targeting and anti-angiogenic antibodies. Imprime PGG combination therapy can trigger a robust, integrated and fully functional innate and adaptive immune response to cancer.

Utilizing whole blood from healthy human donors, Biothera researchers demonstrated that the Imprime PGG-ABA immune complexes activate and become decorated with complement (iC3b). Once formed, these three-part complexes (Imprime-ABA-complement) can then bind to and activate innate effector immune cells. However, these complexes form only in blood from donors who have sufficient levels of ABA (>20 μg/ml), and evidence of innate immune activation in response to Imprime PGG treatment is apparent only in such donors. Importantly, supplementing the whole blood from donors with insufficient ABA levels with purified ABA restores innate immune activation, which highlights the critical nature of sufficient ABA for Imprime PGG responsiveness.

"These data clearly show the necessity of ABA for responsiveness to Imprime-based therapy," said Jeremy Graff, Ph.D., Biothera’s Chief Scientific Officer and Senior Vice President, Research. "We look forward to using ABA levels to identify these biomarker-positive patients in our upcoming Phase 2 clinical trials combining Imprime PGG and immune checkpoint inhibitors."

Biothera plans to conduct a Phase 2 clinical trial to evaluate Imprime PGG and Merck’s anti-PD-1 inhibitor KEYTRUDA (pembrolizumab) in patients with either advanced melanoma or metastatic triple negative breast cancer. The Big Ten Cancer Research Consortium plans to test this therapeutic combination in Phase 1b/2 study in patients with non-small cell lung cancer. Both studies are planned to open enrollment in 2016.

Aduro Biotech Presents Preclinical Data Demonstrating Acute and Systemic Immune Activation through STING Pathway Stimulation with ADU-S100

On November 7, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported an oral presentation given by the company’s chief scientific officer, Thomas Dubensky Jr., Ph.D., at the 4th European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Symposium on Immuno-Oncology held last week in Lausanne, Switzerland (Press release, Aduro BioTech, NOV 7, 2016, View Source [SID1234516350]). The data, generated from multiple preclinical models, demonstrated important changes in the tumor microenvironment and the activation of acute and systemic tumor-specific immune cell responses following intratumoral administration of ADU-S100 (also known as MIW815), an investigational STING (Stimulator of Interferon Genes) Pathway Activator immunotherapy. Importantly, these preclinical data underscore the ability for ADU-S100 to induce tumor-specific memory mediated by immune cells (e.g. T-cells and NK-cells) whereby the immune system is able to eliminate specific cancerous cells upon their reintroduction without further therapy. Additionally, the anti-tumor efficacy achieved with ADU-S100 was enhanced by combination with an anti-PD-1 immune checkpoint inhibitor, and resulted in the complete eradication of local and distal tumors.

"We are pleased to have further validated, through multiple preclinical models, our previous discoveries regarding the potential mechanism of action of the STING Pathway and the role it serves in stimulating a robust and systemic T-cell immune response," stated Dr. Dubensky. "We look forward to working in partnership with Novartis on translating our preclinical findings to a clinical experience as we continue to make progress with our ongoing Phase 1 study of ADU-S100."

Presentation Title: Activation of the STING pathway to induce tumor immunity
In the oral presentation which was given on Saturday, November 5, Dr. Dubensky presented data from preclinical studies using multiple models that demonstrate intratumoral injection of ADU-S100 activates the STING Pathway and induces a durable local and systemic anti-tumor immune response as evidenced by induction of type I interferons (IFNs) and a CD8+ T-cell response. Additionally, preclinical data show the combination of STING activation in the tumor microenvironment and PD-1 blockade enhances antitumor efficacy. There is an ongoing Phase 1 first-in-human dose escalation clinical study to evaluate the safety, tolerability and possible anti-tumor activity of ADU-S100 in patients with cutaneously-accessible advanced metastatic solid tumors or lymphomas. To learn more about this trial, visit www.clinicaltrials.gov.

About the Tumor Microenvironment
The tumor microenvironment is the cellular environment in which the tumor exists, and, along with cancerous cells, includes support cells, immune cells, surrounding blood vessels, and the extracellular matrix. The tumor cells and the surrounding microenvironment are closely related and interact constantly. Tumors influence the microenvironment by releasing signals that promote tumor growth, immune tolerance and immune suppression. When tumors initially form, the body’s immune system recruits and activates a host of immune cells to fight the invading tumor. However, in cases where cancer develops, tumors are eventually able to evade the immune system by changing their microenvironment to inhibit the ability of the immune system to recognize and destroy the tumor thus allowing for tumor outgrowth and formation of metastasis.

About STING Pathway Activator Platform
The Aduro-proprietary STING Pathway Activator product candidates, including ADU-S100 (MIW815), are synthetic small molecule immune modulators that are designed to target and activate human STING. STING is generally expressed at high levels in immune cells, including dendritic cells. Once activated, the STING receptor initiates a profound innate immune response through multiple pathways, inducing the expression of a broad profile of cytokines, including interferons and chemokines. This subsequently leads to the development of a systemic tumor antigen-specific T cell adaptive immune response.

Roche announces initiation of two phase III pivotal trials in melanoma based on results of studies combining targeted and immunotherapy treatment approaches; early data presented at the International Congress of the Society for Melanoma Research

On November 7, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from two early cancer immunotherapy studies at the International Congress of the Society for Melanoma Research (SMR) (Press release, Hoffmann-La Roche, NOV 7, 2016, View Source [SID1234516330]). These early studies of clinical efficacy and safety for combinations including TECENTRIQ (atezolizumab), Cotellic (cobimetinib) and ZelborafTM (vemurafenib), are advancing the development of new treatment approaches while broadening the understanding of melanoma. In addition, three-year data from the phase III coBRIM study were presented, confirming the long-term overall survival benefit of Cotellic plus Zelboraf in BRAFV600 mutation positive advanced or metastatic melanoma.

Safety and efficacy results from 30 patients in a phase Ib study of the combination of TECENTRIQ, an anti-PD-L1 monoclonal antibody, with Cotellic, a MEK inhibitor, plus Zelboraf, a BRAF inhibitor, in previously untreated patients with BRAFV600 mutation-positive metastatic melanoma, were presented. Median safety follow-up was 3.9 months (range 0.7-16.8). Grade 3-4 adverse events (AEs) were seen in 40 percent of patients treated with the triple combination; all resolved after appropriate interventions. No unexpected AEs, Grade 5 AEs or TECENTRIQ-related serious AEs occurred. Out of 29 evaluable patients for efficacy, responses were seen in 24 patients (83 percent) with 3 complete responses and 21 partial responses; the majority of patients continued to respond at the time of data cut-off (median follow up of 5.6 months).

Results were also presented from a phase Ib study of TECENTRIQ with Cotellic, including efficacy and safety data for 22 patients with metastatic melanoma (2 ocular, 20 non-ocular with 10 each BRAF-mutant and wild-type). Patients had received a median of 1 prior therapy for melanoma (range 0-8), but had not received prior anti-PD-1/PD-L1 therapy. Median safety follow-up was 14.0 months (range 2.4-20.2 months). Grade 3-4 AEs occurred in 59 percent of patients, no treatment-related Grade 5 AEs were reported; all AEs were manageable. Among the 20 patients with non-ocular metastatic melanoma the objective response rate (ORR) was 45 percent (50 percent in BRAF wild-type and 40 percent in BRAF-mutant patients). The median progression-free survival (PFS) was 12 months in the non-ocular melanoma patients (15.7 months in BRAF wild-type and 11.9 months in BRAF-mutant patients).

"We are encouraged by these early results which demonstrate a high proportion of people responded to these investigational combination therapies," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The results suggest that the combination of TECENTRIQ with our BRAF and MEK targeted agents may extend the established benefits of the approved monotherapy and combination approaches of these medicines."
Based on the promising results of these Phase Ib studies, Roche plans to initiate two Phase III studies of these investigational combinations for patients with metastatic melanoma. These pivotal trials will study TECENTRIQ with Cotellic plus Zelboraf in treatment-naïve, BRAF-mutant metastatic melanoma and TECENTRIQ with Cotellic in treatment-naïve, BRAF wild-type metastatic melanoma.

Additionally, updated OS data from the phase III coBRIM study of Cotellic plus Zelboraf have demonstrated the continuing benefit across all patient subgroups of the combination therapy vs Zelboraf alone, in patients with BRAFV600-mutation positive unresectable locally advanced metastatic melanoma. The percentage of patients alive at three years was 37.4 percent for people treated with Cotellic plus Zelboraf vs 31.1 percent for patients treated with placebo plus Zelboraf. Median OS was 22.5 months for Cotellic plus Zelboraf vs 17.4 months for Zelboraf alone.
Follow Roche on Twitter via @Roche and keep up to date with SMR 2016 congress news and updates by using the hashtag #SMR16.

About Cotellic and Zelboraf in combination
Zelboraf was the first approved treatment for patients with unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche’s cobas 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma. Cotellic (cobimetinib) is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up the MAPK signaling pathway that helps regulate cell division and survival. In the majority of patients, resistance to BRAF-inhibitor monotherapy will eventually occur through re-activation of the MAPK pathway via MEK. Cotellic was developed to overcome resistance to BRAF-inhibition and prevent re-activation of the pathway. Cotellic binds to MEK, while Zelboraf binds to mutant BRAF, to interrupt abnormal signalling that can cause tumours to grow.
Cotellic is also being investigated in combination with several investigational medicines, including immunotherapy, in several tumour types such as non-small cell lung cancer and colorectal cancer. Cotellic was discovered by Exelixis Inc. and is being developed by Roche in collaboration with Exelixis.

About melanoma
Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer. A V600 mutation of the BRAF protein occurs in approximately half of melanomas, and should therefore be tested to identify the best treatment option. When melanoma is diagnosed early, it is generally a curable disease, but most people with advanced melanoma have a poor prognosis. More than 232,000 people worldwide are currently diagnosed with melanoma each year. In recent years, there have been significant advances in treatment for metastatic melanoma, and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.

Regorafenib from Bayer Submitted to Health Authorities Seeking Approval in Second-Line Treatment of Liver Cancer (for specialized target groups only)

On November 7, 2016 Bayer reported the submission of applications to extend the marketing authorization for its oral multi-kinase inhibitor regorafenib in the U.S., Japan and Europe, for the second line treatment of patients with unresectable hepatocellular carcinoma (HCC)(Press release, Bayer, NOV 7, 2016, View Source [SID1234516327]). Regorafenib is already approved under the brand name Stivarga in many countries to treat metastatic colorectal cancer and metastatic gastrointestinal stromal tumors.

"Almost 10 years ago, we brought Nexavar, the first approved systemic therapy in liver cancer, to patients. We have remained committed to improving the lives of liver cancer patients and are proud that our efforts have yielded a second therapy with an overall survival advantage for patients," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "These filings bring us a step closer to potentially being able to offer a much needed second-line option to liver cancer patients in the near future."

"Approximately 780,000 people are diagnosed with HCC worldwide each year, a number that continues to increase. Regorafenib is the first treatment to successfully deliver an overall survival benefit in the second-line setting for HCC and has the potential to change the treatment paradigm by becoming the new standard of care for patients who progress on sorafenib," said Dr. Jordi Bruix, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain. Dr. Bruix is the Principal Investigator of the RESORCE study as well as the Phase III study SHARP which investigated sorafenib in HCC.

The regulatory submissions for regorafenib are 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.

In the U.S., regorafenib has received Fast Track designation, which is an expedited program designed to facilitate the development, and expedite the review of drugs to address an unmet medical need in the treatment of a serious or life-threatening condition.

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.

About Sorafenib (Nexavar)
Sorafenib, an oral anti-cancer therapy, has been shown in preclinical studies to inhibit multiple kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) – two important processes that enable cancer growth. These kinases include Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Sorafenib is marketed under the brand name Nexavar and is approved for the treatment of certain forms of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC) and differentiated thyroid carcinoma (DTC). Whilst licenses may differ from country to country, across all indications Nexavar is approved in more than 100 countries worldwide. In countries of the EU, Nexavar is approved for the treatment of (HCC); for the treatment of patients with advanced RCC who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy; and for progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

Bayer has worldwide exclusive marketing rights for Nexavar, with Bayer paying a royalty on US sales to Amgen Inc. Outside the U.S., Bayer and Amgen share profits globally, excluding Japan.