On April 19, 2016 Galena Biopharma, Inc. (NASDAQ:GALE), a biopharmaceutical company committed to the development and commercialization of targeted oncology therapeutics that address major unmet medical needs, reported that data from the booster phase of the Company’s GALE-301/GALE-302 Phase 1/2a clinical trial was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Galena Biopharma, APR 19, 2016, View Source [SID:SID1234515197]).

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The poster, entitled, "Comparing an attenuated booster (E39’) vs. E39 booster to potentiate the clinical benefit of the folate binding protein (FBP)-derived vaccine (E39 + GM-CSF) in a phase I/IIa trial to prevent recurrence in endometrial (EC) and ovarian cancer (OC) patients," was presented today by Dr. Doreen Jackson from the San Antonio Military Medical Center. In the Phase 2a portion of the trial, patients were randomized to two different boosters: E39 (GALE-301), versus E39’ (GALE-302). The purpose of the study was to evaluate the immune responses and determine which booster, if either, would provide a sustained immune response and potentially longer disease free survival (DFS) rates.

The use of the wildtype peptide (GALE-301/E39) demonstrated the same tolerable safety profile as the attenuated peptide (GALE-302/E39’) with only Grade 1 local reactions and minimal Grade 2 toxicities. Importantly, the percentage of patients who received two booster inoculations and remained disease free was significantly better in the drug treatment arm, versus the control arm (p=0.02), regardless of which booster was used. At median follow up of 16 months, the boosters demonstrated equivalent efficacy after two booster inoculations with an estimated, two-year DFS rate of 66.7% (GALE-301 n=7, GALE-302 n=7) in each booster arm versus 36% (n=22) in the control arm.

"In our GALE-301 Phase 2a trial, we randomized patients to determine an optimal boosting strategy and to see if there was an observable difference between boosting patients with GALE-301 versus the attenuated version of the peptide, GALE-302," stated Bijan Nejadnik, M.D., Executive Vice President and Chief Medical Officer. "The results show that both boosters were effective with no measurable difference between them, and we will consider this as we continue to evaluate the best path forward for our compounds targeting FBP. The primary analysis of this trial will be presented at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in June."

A total of 51 patients were enrolled in the Phase 1/2a trial with 29 HLA-A2-positive patients in the vaccine group (VG) and 22 HLA-A2-negative patients in the control group (CG). Six monthly intradermal inoculations of GALE-301 plus 250mcg GM-CSF were administered to the VG to complete the primary vaccine series (PVS). Patients were then randomized to receive two booster inoculations of 500mcg of GALE-301 or GALE-302 plus 250mcg GM-CSF at six and twelve months post-PVS. Seventeen patients continued onto the booster series and were randomized with 14 receiving two boosters. There were no significant demographic or baseline differences between groups, no difference in toxicities were observed, and there were no Grade 3 or 4 toxicities in either group.

About GALE-301 and GALE-302
GALE-301 and GALE-302 are cancer immunotherapies that consist of a peptide derived from Folate Binding Protein (FBP) combined with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF) for the prevention of cancer recurrence in the adjuvant setting. GALE-301 is the E39 peptide, while GALE-302 is an attenuated version of this peptide, known as E39’. FBP is a well-validated therapeutic target that is highly over-expressed in ovarian, endometrial and breast cancers, and is the source of immunogenic peptides that can stimulate cytotoxic T lymphocytes (CTLs) to recognize and destroy FBP-expressing cancer cells. Two trials are ongoing with FBP peptides in gynecological cancers: the GALE-301 Phase 2a portion of the Phase 1/2a clinical trial is ongoing in ovarian and endometrial adenocarcinomas (ClinicalTrials.gov Identifier: NCT01580696); the GALE-301 plus GALE-302 Phase 1b clinical trial is ongoing in breast and ovarian cancers (ClinicalTrials.gov Identifier: NCT02019524).

About Ovarian/Endometrial Cancers
New cases of ovarian cancer occur at an annual rate of 12.1 per 100,000 women in the U.S., with an estimated 21,290 cases for 2015. Although ovarian cancer represents about 1.3% of all cancers, it represents about 2.4% of all cancer deaths, or an estimated 14,180 deaths in 2015. Approximately 1.3% of women will be diagnosed with ovarian cancer at some point during their lifetime (2010 – 2012 data). The prevalence of ovarian cancer in the U.S. is about 192,000 women, and the five-year survivorship for women with ovarian cancer is 45.6%.

Due to the lack of specific symptoms, the majority of ovarian cancer patients are diagnosed at later stages of the disease, with an estimated 75% of women presenting with advanced-stage (III or IV) disease. These patients have their tumors routinely surgically debulked to minimal residual disease, and then are treated with platinum- and/or taxane-based chemotherapy. While many patients respond to this treatment regimen and become clinically free-of-disease, the majority of these patients will relapse. Depending upon their level of residual disease, the risk for recurrence after completion of primary therapy ranges from 60% to 85%. Unfortunately for these women, once the disease recurs, treatment options are limited and the disease remains incurable.
New cases of endometrial cancer occur at an annual rate of 25.1 per 100,000 women in the U.S., with an estimated 54,870 cases for 2015. Although endometrial cancer represents about 3.3% of all cancers, it represents about 1.7% of all cancer deaths, or an estimated 10,170 deaths in 2015. Approximately 2.8% of women will be diagnosed with endometrial cancer at some point during their lifetime (2010 – 2012 data). The prevalence of endometrial cancer in the U.S. is about 620,000 women, and the five-year survivorship for women with endometrial cancer is 81.7%.

Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.Oncogene advance online publication, 18 April 2016; doi:10.1038/onc.2016.114.

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On April 19 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported that clinical data of a dendritic cell (DC) vaccine trial for the treatment of prostate cancer were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, USA (Press release, MediGene, APR 19, 2016, View Source [SID:1234511089]).

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The clinical data were collected, utilising Medigene’s DC vaccine technology in part, in an ongoing clinical phase I/II study on dendritic cell (DC) vaccines for the treatment of prostate cancer at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presented was entitled "Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin".

More than 50% of high risk prostate cancer patients will develop an early biochemical relapse, with no curative therapy presently available. Therefore, Prof. Gunnar Kvalheim and his team have chosen this patient population for their ongoing Phase I/II dendritic cell (DC) vaccine study. Dendritic cells from each of the 20 enrolled patients were differentiated from enriched monocytes and matured with one of two different maturation cocktails. The DCs were then transfected with mRNA from primary prostate cancer tissue, hTERT and Survivin and then frozen and stored until use. Based on encouraging clinical results with a new type of DCs in patients with different types of tumours treated in a compassionate use[1] programme, the DC vaccine protocol was changed to the use of new generation DCs. The last five of 20 treated patients received DCs that were matured with a new TLR7/8-agonist maturation cocktail developed by Medigene. Three of 15 patients given DC vaccines derived with the old (standard) maturation cocktail have experienced a biochemical relapse (raised levels of prostate-specific antigen, PSA) during the vaccination period of 3 years. None of the patients given the new type of DC vaccines has so far experienced a rise in PSA levels.

Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital concluded on the results: "To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising."

Prof. Dolores J. Schendel, CEO/CSO of Medigene AG added: "We feel very encouraged by these preliminary data. The advanced method of making DC vaccines is identical with the method Medigene is also using in its own ongoing DC vaccine study in acute myeloid leukaemia."

More detailed information on the presented data can be found under the following link: View Source;sKey=ac456e79-efd5-416e-a7de-67382c67723a&cKey=2ab5cd11-b3d8-40a8-8087-b0c57f2e8034&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced platform of the highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. 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): a clinical phase I/II trial for treating acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical phase II trial of a treatment for prostate cancer at Oslo University Hospital. Moreover, compassionate use 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 GmbH’s scientists has developed new, fast and efficient methods for generating dendritic cells ex-vivo, which have relevant characteristics 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 use in combination therapies.

RG7876 is a fully human (IgG2) agonistic antibody against CD40 (Company Pipeline, Hoffmann-La Roche , APR 19, 2016, View Source [SID:1234512462]). The antibody induces T cell-driven tumor killing by activation of CD40 on antigen-presenting cells which in turn prime T cells to attack the tumor. The antibody is being developed in combination with other immunotherapies and is currently being tested in combination with atezolizumab (anti-PD-L1, RG7446).

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On April 19, 2016 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs through molecular design imparting multiple target-selected inhibition, reported the presentation of scientific data on the company’s dual small-molecule PI3K/BRD4 inhibitor program in oncology (Press release, SignalRx, APR 19, 2016, http://www.ireachcontent.com/news-releases/signalrx-presents-at-aacr-annual-meeting-on-first-in-class-dual-pi3kbrd4-inhibitors-for-treating-cancer-576189881.html [SID1234527327]). The presentation by Dr. Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, was made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

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The presentation highlighted advancements in the development of SF2523, SF2535 and SF2558HA, all single small molecules that inhibit both PI3 kinase (PI3K) and the new epigenetic cancer target BRD4. Key breakthroughs are:

New crystal structures obtained for SF2523, SF2535 and SF2558HA with BRD4 protein providing insights on key dual inhibitor binding interactions.
First-time proof of MYC inhibition by enhancing MYC degradation via PI3K inhibition AND blocking MYC production via MYC transcription inhibition (BRD4 inhibition).
SF2523 exhibits desired in vivo anti-tumor effects with no toxicity in several mouse cancer models.
Inhibition of PI3K-gamma and delta isoforms by SF2523 function as checkpoint inhibitors and enhance immune-therapeutics.
BRD4 inhibition blocks tumor-specific super-enhancers activating the innate and adaptive immune response providing a novel strategy to treat cancer.
The company also demonstrated that SF2523 is safer to normal cells over the combination of single PI3K and BRD4 inhibitors making SF2523 an attractive anti-cancer candidate that can potentially overcome traditional toxicity issues associated with most combinations of oncology drugs.

SignalRx is also announcing that it is seeking a partner to accelerate the development of these novel small molecules into first-in-man clinical trials based on the promising profile of its PI3K/BRD4 inhibitors shown so far. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to develop them as single therapeutics and streamline their development in combination therapies focused on companion diagnostics built around synthetic lethality discoveries in human cancers, e.g., kinome adaptation mediated by BRD4.