On April 21, 2016 TapImmune,Inc. (TPIV), a clinical-stage immunology-oncology company specializing in the development of innovative peptide and gene-based immunotherapeutics and vaccines for the treatment of cancer & metastatic disease, reported plans to initiate a Phase 2 trial of its cancer vaccine, TPIV 200, a multi-epitope anti-folate receptor vaccine (FRalfa), in combination with Astra Zeneca (NYSE: AZN) durvalumab (MEDI4736), an anti-PD-L1 antibody, in patients with platinum-resistant ovarian cancer (Press release, TapImmune, APR 21, 2016, View Source [SID:1234512243]). The study will commence in the second quarter of 2016 at Memorial Sloan Kettering Cancer Center in New York and will be led by Jason Konner, M.D. as Principal Investigator.

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The two Companies will share clinical costs, while TapImmune will supply TPIV 200 and MedImmune will supply Durvalumab (MED14736) for the trials. TapImmune recently obtained Orphan Drug Designation for TPIV 200 in ovarian cancer from the U.S. Food and Drug Administration.

This single arm Phase 2 trial will include 40 women with high-grade ovarian, tubal, or primary peritoneal carcinomas, who have progressed within 6 months of their most recent platinum chemotherapy. The primary objective of the study is to determine the effectiveness of the combination by measuring Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST and Progression Free Survival (PFS) rate at 6 months. Secondary endpoints will be safety and immune and correlation of FRalfa-specific immune responses with clinical efficacy.

"This collaboration is a significant event for TapImmune," stated Dr. Glynn Wilson, Chairman and CEO of TapImmune. "We are delighted to bring a leading T-cell vaccine platform into this combination study and to work with AstraZeneca/Medimmune and Sloan Kettering in a patient population that is in dire need of an effective treatment."

"This study is part of a larger Phase 2 strategy for TPIV 200 that is designed to greatly increase our understanding of the vaccine while providing clinical evidence of efficacy," Dr. Wilson added.

TPIV 200 is a multi-epitope peptide vaccine that targets Folate Receptor Alpha, which is overexpressed in multiple cancers including over 90% of ovarian cancer cells. In Phase I clinical studies conducted at the Mayo Clinic in patients with breast and ovarian cancer, this vaccine was shown to be safe and well tolerated and to give robust cellular immune responses in 20 out of 21 evaluable patients.

About Durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against PD-L1 developed at MedImmune LLC. Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, gastric, pancreatic, bladder and blood cancers.

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation.
Copyright © 2015 Elsevier Ltd. All rights reserved.

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New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

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On April 21, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that researchers from the Icahn School of Medicine at Mount Sinai, led by Professor E. Premkumar Reddy, scientific founder of Onconova, have published a study describing the novel RAS-targeted mechanism of action for rigosertib in the journal Cell (Press release, Onconova, APR 21, 2016, View Source [SID:1234511258]). The paper, titled "A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling," can be accessed in the current online edition of Cell.

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RAS represents one of the most sought-after targets in cancer. Thus far the development of drugs to block RAS has been difficult, leading many to label RAS the undruggable oncogene.

"This discovery is the culmination of my laboratory’s work with RAS genes over the last three decades," said Dr. E. Premkumar Reddy, lead author of the paper and Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. "RAS genes have been a challenging target for molecular oncologists and drug developers. However, the allosteric mechanism by which rigosertib blocks activation of signaling proteins downstream of RAS may represent a new paradigm for attacking this oncogene."

The research published in Cell and carried out by a multidisciplinary team from Mount Sinai, The Scripps Cancer Research Institute, Albert Einstein College of Medicine, and the New York Structural Biology Center, demonstrated that rigosertib blocks RAS signaling by directly binding to various RAS effector proteins, including RAF and PI3-kinase. These mechanistic findings support the development of rigosertib in malignancies with over-activate RAS signaling, such as higher-risk myelodysplastic syndromes (HR-MDS). Onconova is actively enrolling patients in the global INSPIRE trial, a randomized Phase 3 study to assess the efficacy and safety of single-agent intravenous rigosertib in HR-MDS.

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

About RAS

Point mutations in RAS genes (HRAS, KRAS and NRAS) are frequently observed in many of the most common and lethal tumors, including cancers of the pancreas, lung, colon, skin, bladder and bone marrow. RAS genes encode important intracellular proteins that when mutated activate pathways involved in cancer cell proliferation, survival and metastasis. Although molecular oncologists have made significant headway in understanding RAS mutations and their impact on cellular signaling, less progress has been made towards developing RAS-targeted drugs. Thus, there is an urgent need for new therapeutic modalities that address this important oncogene.

The widespread adoption of electronic health records (EHRs) and the growing wealth of digitized information sources about patients is ushering in an era of ‘Big Data’ that may revolutionize clinical research in oncology. Research will likely be more efficient and potentially more accurate than the current gold standard of manual chart review studies. However, EHRs as they exist today have significant limitations: important data elements are missing or are only captured in free text or PDF documents. Using two case studies, we illustrate the challenges of leveraging the data that are routinely collected by the healthcare system in EHRs (e.g., real-world data), specific challenges encountered in the cancer domain and opportunities that can be achieved when these are overcome.

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