On December 11, 2018 Alligator Bioscience AB (Nasdaq Stockholm: ATORX) reported that regulatory approvals have been obtained for the first clinical study of ATOR-1015 and patient recruitment can now be initiated. ATOR-1015 is a wholly-owned drug candidate developed for tumor-directed immunotherapy (Press release, Alligator Bioscience, DEC 11, 2018, View Source [SID1234538673]).

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The phase I study is a first-in-human dose-escalation study in up to 53 patients with advanced solid tumor disease at five different clinics across Sweden and Denmark. The primary aim of the study will be to investigate the safety and tolerability of the drug and to identify the recommended dose for subsequent Phase II studies.

"The start of clinical phase I study with ATOR-1015 represents a significant milestone for Alligator. We are first in the world with a new concept, a tumor-localizing bispecific CTLA-4 antibody. While the target is clinically validated, the clinical use of CTLA-4 blocking agents is restricted by severe toxicity. ATOR-1015 may provide a solution through its potential for selective activation of the immune system in the tumor area but not elsewhere in the body. The drug’s preclinical results are very promising, clearly supporting this concept", said Per Norlén, CEO of Alligator Bioscience.

As previously communicated, Alligator has appointed Theradex Oncology, a global contract research organization with extensive expertise in oncology clinical development, to conduct the phase I study.

For further information, please contact:
Cecilia Hofvander, Director Investor Relations & Communications
Phone +46 46 540 82 06
E-mail: [email protected]

This information is such information as Alligator Bioscience AB (publ) is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person set out above, at 8:00 a.m. CET on December 11, 2018.

About ATOR-1015
ATOR-1015 is a next generation CTLA-4 bispecific antibody developed for tumor-directed immunotherapy with increased capability of regulatory T-cell depletion. It is wholly-owned by Alligator. ATOR-1015 binds to two different immune receptors: the checkpoint receptor CTLA-4 and the co-stimulatory receptor OX40. The immune activation is increased in areas where both target molecules are expressed at high levels, notably in the tumor microenvironment, which is believed to reduce adverse immune reactions.

On December 11, 2018 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported the initiation of the triple combination arm of the Phase 2a COMBAT/KEYNOTE-202 study in patients with metastatic pancreatic cancer (PDAC) under its immuno-oncology collaboration with Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada) (Press release, BioLineRx, DEC 11, 2018, View Source;p=irol-newsArticle&ID=2380207 [SID1234532008]). As previously announced, the triple combination arm will investigate the safety, tolerability and efficacy of BL-8040, KEYTRUDA and chemotherapy.

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The triple combination arm will focus on second-line pancreatic cancer patients, and will include approximately 40 patients with unresectable metastatic pancreatic adenocarcinoma who have progressed following first-line therapy prior to enrollment. Patients will receive BL-8040 monotherapy priming treatment for 5 days, followed by ongoing cycles of the combination of chemotherapy (Onivyde/5-fluorouracil/leucovorin – 5-FU/LV), KEYTRUDA and BL-8040 until progression. The primary endpoint of the study is the objective response rate (ORR) assessed by RECIST v1.1 criteria. Secondary endpoints will include overall survival, progression free survival, and the disease control rate.

"We are pleased to commence this triple combination arm of our Phase 2a pancreatic study, under the framework of our immuno-oncology collaboration with MSD," stated Philip Serlin, Chief Executive Officer of BioLineRx. "We believe that the addition of chemotherapy may be synergistic with BL-8040 and KEYTRUDA, as chemotherapy has been shown to reduce overall tumor burden while inducing immunogenic cell death, leading to activation and expansion of new tumor-reactive T-cells. Based on its mechanism of action, we believe that BL-8040 may facilitate the infiltration of these T-cells into the tumor core, alongside the restoration of T-cell activity within the tumor by KEYTRUDA. We look forward to results of the study expected in the second half of 2019."

At the recent European Society for Medical Oncology 2018 Congress in Munich, Germany, BioLineRx disclosed top-line results from the dual combination arm of the Phase 2a COMBAT/KEYNOTE-202 study, evaluating PDAC patients treated with BL-8040 in combination with KEYTRUDA. The results show encouraging disease control and extended overall survival, particularly in patients undergoing second-line treatment. In addition, the data also demonstrate that BL-8040 significantly improves T-cell infiltration into the tumor and reduces immunosuppression in the tumor microenvironment.

About the COMBAT/KEYNOTE-202 Study

The Phase 2a COMBAT/KEYNOTE-202 study was originally designed as an open-label, multicenter, single-arm trial to evaluate the safety and efficacy of the combination of BL-8040 and KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study was primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies, and was carried out in the US, Israel and additional territories. The study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary.

In July 2018, the Company announced the expansion of its immuno-oncology collaboration with MSD to include a triple combination arm investigating the safety, tolerability and efficacy of BL-8040, KEYTRUDA and chemotherapy as part of the Phase 2a COMBAT/KEYNOTE-202 study. The triple combination arm will focus on second-line pancreatic cancer patients.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells to peripheral blood and to be effective at inducing direct tumor cell death. In addition, clinical findings have demonstrated the ability of BL-8040 to mediate infiltration of T-cells into tumors that were previously immunologically "cold" and devoid of immune cell infiltrate. Immune checkpoint inhibitors (such as KEYTRUDA) produce anti-cancer effects by increasing the activity of T-cells through blockade of the interaction between the immune checkpoint receptor PD-1, on T-cells, and its ligand PD-L1, on tumor cells. Pancreatic cancers have very little T-cell infiltrate, making them less susceptive to checkpoint blockade than other tumors that are infiltrated by T-cells. Therefore, combining BL-8040 with immune checkpoint blockade is predicted to increase the responsiveness of pancreatic cancer patients to immunotherapy. Further increase in the sensitivity of pancreatic cancer cells to BL-8040 and KEYTRUDA may be achieved by chemotherapy-mediated immunogenic cell death and exposure of new tumor antigens, resulting in activation of new anti-cancer T cell clones.

About BL-8040

BL-8040 is a short synthetic peptide for the treatment of hematological malignancies, solid tumors, and stem cell mobilization. It functions as a high-affinity best-in-class antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells and immune-cells, sensitization of cancer cells to chemo- and bio-based anti-cancer therapies, and direct anti-cancer effect by inducing programmed cell death (apoptosis). BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

On December 11, 2018 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing intratumoral cancer immunotherapies, reported the presentation of new data that suggests treatment with TAVO (tavokinogene telseplasmid) has the ability to improve immune responses in heavily pretreated, inoperable and locally advanced triple negative breast cancers by increasing tumor infiltrating lymphocyte (TIL) density, increasing effector cytokines, and upregulating immune-related gene expression, factors associated with long-term response to anti-PD1 antibodies (Press release, OncoSec Medical, DEC 11, 2018, View Source [SID1234532009]).

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The now completed Pilot TNBC study, OMS-140 (NCT02531425), was designed to determine whether a single cycle of TAVO monotherapy could enhance anti-tumor immune responses in a TNBC salvage setting. Specifically, a comparative analysis of patient’s pre-TAVO tumor and blood samples to the post-TAVO tumor and blood samples demonstrated that, with only a single cycle of TAVO, a treatment-related increase of CD8+ TIL was observed in four of 10 patients, while also demonstrating a relative decrease in immune suppressive cells.

Nanostring analysis (a novel platform for quantification of gene expression) of the tumor microenvironment revealed a meaningful increase of immune-related transcripts while on treatment. The investigator also evaluated the peripheral blood through a longitudinal analysis of PBMCs (peripheral blood mononuclear cells), and, in doing so, noted an increase of both effector and partially exhausted T cells, which complements the reduced frequency of immune-suppressive MDSC (myeloid-derived suppressor cells) reported earlier this year at AACR (Free AACR Whitepaper).

These data, along with increased effector cytokines noted in serum, demonstrate both local and systemic immune responses with only one cycle of TAVO in this difficult to treat patient population. Additionally, as observed in other clinical trials with TAVO, this study showed that TAVO is safe and well tolerated in this patient population.

These data, as well as other clinical and immunological data, were presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) taking place December 4-8 in San Antonio, Texas.

"The immunological signatures described here, including conversion of non-immunogenic tumors into immunologically active lesions, are very encouraging, especially when considering that patients with very advanced disease received only one cycle of TAVO," said Dr. Christopher Twitty, Chief Scientific Officer of OncoSec. "Late-stage triple negative breast cancer patients have very few treatment options, and those that are available, come with serious toxicities and limited effectiveness. Recent data suggest that some patients with triple negative tumors will benefit from treatment with PD-1 checkpoint inhibitors, but only if the patient’s tumor is immunologically active," continued Dr. Twitty. "This study represents the potential of a safe and effective immunotherapy to turn non-immunogenic tumors into an immunologically active tissue, expanding the benefits of PD-1 checkpoint inhibitors to a much broader subset of women with triple negative breast cancer, which would be an important advance for the treatment of these patients."

As previously reported, a subset of patients that completed a single cycle of TAVO in this study, were sequentially treated with an anti-PD-1 checkpoint therapy (nivolumab). Importantly, some of these patients, one with prior disease progression on anti-PD-L1 antibody monotherapy, experienced robust clinical responses beyond the TAVO treated lesions. One of these patients continues to be treated with TAVO under a compassionate use protocol.

Based on these findings, OncoSec and Merck initiated a second TAVO Phase 2 study in TNBC, KEYNOTE-890, to evaluate the combination of TAVO with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in approximately 25 patients with treatment-refractory, inoperable or metastatic triple negative breast cancer (NCT03567720).

Since KEYNOTE-890 opened in October, investigators have already enrolled five patients into the trial. The KEYNOTE-890 study is testing the combination in patients with inoperable locally advanced or metastatic TNBC who have progressed on more than one line of prior therapy. Patients will be treated with the combination of TAVO with pembrolizumab. The primary endpoint is to assess efficacy as measured by objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

On December 11, 2018 PharmaCyte Biotech, Inc. (OTCQB: PMCB), reported a biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, released an interview with Lyon Gleich, M.D., of Medpace, a global full-service clinical contract research organization (CRO) (Press release, PharmaCyte Biotech, DEC 11, 2018, View Source [SID1234532010]). Dr. Gleich serves as the Medical Monitor and key team member of PharmaCyte’s planned clinical trial in locally advanced, inoperable pancreatic cancer (LAPC).

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Dr. Gleich is Vice President, Medical Oncology, at Medpace headquartered in Cincinnati, Ohio. Dr. Gleich has provided medical leadership over oncology trials at Medpace for nearly 15 years. He has extensive expertise in new drug development in oncology—specifically, pancreatic cancer.

Why is Medpace well suited to conduct PharmaCyte’s clinical trial in locally advanced, non-metastatic, inoperable pancreatic cancer?

Dr. Lyon Gleich: "Medpace is experienced in managing oncology trials of new molecular entities for our biotech partners and our full-service, scientific-model aligns well with innovative companies such as PharmaCyte. Oncology is a clear and well-established focus of Medpace with multiple recent trials in pancreatic cancer. We have strong relationships with oncology sites and site investigators who will help us recruit the best site investigators for this trial. This will also provide patients access to the trial by having multiple sites throughout the United States. Medpace will work with the Principle Investigator and site investigators to maximize their regional referral networks, as well as to support recruitment for PharmaCyte’s study.

"Conducting a pancreatic cancer study is not like managing a study in more benign conditions, where you can advertise for patients. Working with established cancer centers of excellence that have access to pancreatic cancer patients will be critical to the trial’s success. Our relationships with these sites and site investigators, as well as our processes, will enable us to support the site relationships while making sure that the data quality is high and that the trial is run correctly. Medpace will also support the site’s recruitment efforts and trial management to make it as easy as possible for each site and its patients to participate in the trial."

What is unique about PharmaCyte’s signature live-cell encapsulation technology, Cell-in-a-Box?

Dr. Lyon Gleich: "Given the severe mortality rate associated with pancreatic cancer as well as the morbidity of the locally advanced disease, we are eager to work with PharmaCyte to advance their live-cell encapsulation therapy that can potentially improve local morbidity as well as impact survival for patients suffering from this aggressive disease. The Cell-in-a-Box or ‘CypCaps’ capsules that are implanted into each patient will activate the chemotherapy agent ifosfamide in the pancreatic tumor bed specifically, which will permit an infusion of only a low dose of the chemotherapeutic agent PharmaCyte uses for its pancreatic cancer therapy. This is a novel way to take an older and effective chemotherapeutic product and make it even more efficacious. PharmaCyte’s therapy offers LAPC patients a drug with proven anti-cancer activity that is delivered locally to their advanced cancer.

"The CypCaps will require angiographic administration into the pancreatic cancer feeding vessel. Medpace will train each trial site regarding the implantation of the capsules into the patient to ensure proper and consistent methodologies across the study. This will help ensure that the implantation is done without any adverse events and maximize the potential for efficacy of the chemotherapy agent ifosfamide."

What are your thoughts about PharmaCyte and Medpace teaming up with well-known and respected pancreatic cancer experts such as Dr. Manuel Hidalgo?

Dr. Lyon Gleich: "PharmaCyte and the experience of Medpace with pancreatic cancer experts will be key to driving success in this trial. It is important to have the support of the thought leaders in pancreatic cancer that have already been involved with PharmaCyte so that the best sites are recruiting appropriate patients for the study and the quality of the CypCaps administration is done consistently.

"Manuel Hidalgo, M.D., of Beth Israel Deaconess Medical Center, is the Principal Investigator and a well-known expert in pancreatic cancer with whom Medpace is experienced. This is an excellent example of teaming and collaborating with the best resources in treating pancreatic cancer."

How do the CRO and the PI work together during clinical trials?

Dr. Lyon Gleich: "Medpace works to be as supportive and transparent as possible with the Principle Investigator and the site investigators alike. This includes providing training on all protocol procedures and helping sites understand the purpose and details of the study to present it accurately to potential patients. Medpace physicians and staff are readily available to the sites to support and answer trial-related questions and concerns, and thereby help continuously with enrollment and patient treatment in accordance with the protocol. Of course, one of our main responsibilities is also site monitoring to ensure that data is entered in a timely manner and supported at all times by proper site documentation to support any future applications for Marketing Authorization."

What are some of the biggest challenges you anticipate and are planning for in this trial?

Dr. Lyon Gleich: "Any trial in pancreatic cancer is a difficult trial because of the severity and morbidity of the disease. Many patients enrolled in these studies, even if they have a good performance status and high activity level, are patients with advanced cancer with a very high mortality rate. Patients can turn the corner at any moment, in a very negative way, in terms of having a severe worsening of their disease such as an increase in ascites, a blockage of their biliary duct, and even in some cases, a quick descent to death. This is a huge hurdle for any trial in pancreatic cancer. Even during the couple of weeks during the screening period, LAPC patients can see a rapid progression of the disease and are no longer able to respond to any therapy.

"In this trial, we are hopeful that we won’t experience too much of that. The trial is designed for patients with locally advanced non-metastatic unresectable pancreatic cancer. Many patients with pancreatic cancer do have metastatic disease, meaning the spread of the cancer elsewhere in the body, not just a locally advanced disease. This therapy won’t offer a benefit to those patients and is designed for the non-metastatic locally advanced patient. We need to find locally advanced patients without metastases who still have an acceptable performance status and haven’t, so to speak, gone over the precipice where the disease takes off in a way that therapies can no longer help.

"The support of the patients by the treating physicians, their teams and nurses are key to this. Medpace will work closely with PharmaCyte to provide support and education to the teams so that they can provide that needed support and education to the patients to help them through this terrible disease.

"Based on Medpace’s experience in trials with pancreatic cancer and our experience in working with sites in similar difficult studies for late stage advanced pancreatic cancer, we are well positioned to know what the sites expect from us regarding support. Through this important trial, our hope is being able to advance the treatment of pancreatic cancer, which is greatly needed."

About Medpace

Medpace is a scientifically-driven, global, full-service clinical contract research organization (CRO) providing Phase I-IV clinical development services to the biotechnology, pharmaceutical, and medical device industries. The mission of Medpace is to accelerate the global development of safe and effective medical therapeutics through its high-science and disciplined operating approach that leverages local regulatory and deep therapeutic expertise across all major areas including oncology, cardiology, metabolic disease, endocrinology, central nervous system and anti-viral and anti-infective

On December 10, 2018 AstraZeneca reported a new collaboration with Cancer Research UK to launch a centre of excellence in genetic screening, cancer modelling and big data processing aimed at accelerating the discovery of new cancer medicines (Press release, AstraZeneca, DEC 10, 2018, View Source [SID1234531979]). The Functional Genomics Centre will further develop CRISPR technology to better understand the biology of cancer, creating biological models that may be more reflective of human disease, and advancing computational approaches to better analyse big datasets. These approaches are designed to inform new druggable targets in oncology by using clinical insights to better understand tumour disease and resistance mechanisms.

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Functional genomics aims to understand the complex relationship between genetic changes happening within DNA and how these translate to cellular changes in disease. Knowing the functional genomic drivers of disease enables scientists to more accurately select the right drug targets and increases the probability of success in the clinic.

Mene Pangalos, Executive Vice President, Innovative Medicines & Early Development, AstraZeneca, said: "The best science doesn’t happen in isolation which is why AstraZeneca is committed to advancing innovative science through collaboration. This new centre of excellence with Cancer Research UK will combine our expertise in functional genomics and CRISPR technology to identify new biological pathways driving disease and will accelerate the development of new cancer medicines for patients."

Dr Iain Foulkes, Cancer Research UK’s Executive Director of Research and Innovation, said: "We’re delighted to collaborate with AstraZeneca on this exciting new initiative which will give leading Cancer Research UK scientists and our alliance partners access to the latest in CRISPR technology. As we move into an era of personalised medicine, we’ve reached a turning point in our ability to harness powerful technologies in the pursuit of targeted cancer therapies. We hope that this will translate into urgently needed new therapies for patients with hard to treat cancers such as lung, pancreatic, oesophageal and brain tumours."

The Functional Genomics Centre will be located at the Milner Therapeutics Institute at the University of Cambridge. AstraZeneca and Cancer Research UK will have independent use of the Centre’s facilities, and their scientists will work alongside each other to facilitate collaboration, technical innovation and scientific progress.

At the Centre, scientists will have access to the next generation of CRISPR libraries for silencing or activating every gene in the genome, accessed through an extension of the existing collaboration between AstraZeneca and the Wellcome Sanger Institute. This collaboration includes access to the Wellcome Sanger Institute’s most recent versions of human and mouse genome-wide CRISPR/Cas9 knockout libraries, as well as Cas9 and dual gRNA expression vectors. This extends the application of CRISPR technology with vectors, providing enhanced sensitivity and specificity in gene editing, leading to easier targeting and identification.

A separate collaboration between AstraZeneca and the California-based Innovative Genomics Institute (IGI) will aim to use CRISPR to uncover genes and disease pathway mechanisms involved in DNA Damage Response (DDR), a key process involved in many cancers and one of AstraZeneca’s four key platforms in oncology. Research will focus on identifying potential therapeutic strategies for DDR inhibitors, including combinations, in oncology.