On April 19, 2016 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported the presentation of preclinical data from five programs at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, MacroGenics, APR 19, 2016, View Source [SID:1234511059]). Four of the five presented posters were from studies based on MacroGenics’ Dual-Affinity Re-Targeting, or DART, bispecific technology. MacroGenics also presented data from its preclinical anti-B7-H3 antibody-drug conjugate program within the company’s B7-H3 franchise.

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"MacroGenics is encouraged by the promising preclinical data from these five programs," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "With a focus on developing innovative medicines for patients in need, our company is bolstered by early-stage, positive preliminary data from these programs targeting various cancers. With eight molecules in clinical development across immuno-oncology and autoimmune disorders today and plans to expand into infectious diseases, the MacroGenics team is making progress towards our mission of bringing new breakthrough treatments to patients suffering from a range of diseases."

MacroGenics AACR (Free AACR Whitepaper) 2016 Poster Presentations

Each of MacroGenics’ poster presentations described below may be accessed under "Events & Presentations" in the Investors section of the company’s website at View Source

B7-H3 Franchise: As previously reported, MacroGenics is developing a portfolio of therapeutics that target B7-H3, a member of the B7 family of molecules involved in immune regulation, through complementary mechanisms of action that also take advantage of the antigen’s broad expression across multiple solid tumor types. In the presentation titled "Anti-B7-H3 antibody-drug conjugates as potential therapeutics for solid cancer," MacroGenics evaluated the therapeutic potential of anti-B7-H3 antibody-drug conjugates (ADCs) in multiple in vitro and in vivo tumor cell line cases representing human cancer types that overexpress B7-H3. Several anti-B7-H3 ADCs exhibited specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro and in vivo, including breast, lung, ovarian, pancreatic, and prostate cancer lines as well as melanoma. The study results show the potential of B7-H3-targeted ADCs for the treatment of solid cancers that express B7-H3.

MGD013: MGD013, a compound developed using MacroGenics’ DART platform, is a single agent designed to block PD-1 and LAG-3, two immune checkpoint molecules that are co-expressed on T cells. Published work in nonclinical models has shown that combining LAG-3 blockade with PD-1 checkpoint inhibition can further boost the anti-tumor response observed with anti-PD-1 alone. In the presentation titled "MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART) protein with T-cell immunomodulatory activity for cancer treatment," MacroGenics demonstrated that MGD013 has the potential to promote anti-tumor activity by simultaneously blocking both PD-1 and LAG-3. In the study, monoclonal antibodies (mAbs) against PD-1 and LAG-3 were engineered into MGD013, an Fc-bearing DART molecule. MGD013 was shown to block PD-1/PD-L1, PD-1/PD-L2 and LAG-3/MHC-II interactions to levels comparable to those observed with its independent constituents. Furthermore, MGD013 enhanced T-cell response (upon antigen re-challenge), as measured by cytokine secretion, to an extent greater extent than that observed with the independent blockade of each pathway or even when both pathways were inhibited with a combination of anti-PD-1 and anti-LAG-3 mAbs. The results of the study helped support further clinical development of MGD013. MacroGenics plans to submit an Investigational New Drug (IND) application for MGD013 in 2017.

ROR1 x CD3 DART: The receptor tyrosine kinase-like orphan receptor 1, ROR1, is overexpressed in chronic lymphocytic leukemia and a subset of solid tumors, including lung, breast, ovarian, colon, sarcoma and pancreatic cancers. In the presentation titled "Development of a humanized ROR1 x CD3 bispecific DART molecule for the treatment of solid and liquid tumors," MacroGenics demonstrated that a ROR1 x CD3 DART molecule was able to kill ROR1-expressing target cells in vitro. T-cell activation and cytokine release was strictly mediated upon target antigen engagement and not observed with leukocytes alone. The DART molecule also demonstrated anti-tumor activity in vivo, with high response rates in several mouse tumor xenograft models. The promising in vitro and in vivo study results support continued research on the use of ROR1 x CD3 DART molecules as a potential treatment option for cancer patients.

IL13Rα2 x CD3 DART: IL13Rα2 is a membrane-bound protein that has been found to be expressed in malignant tumors. "Development of an IL13Ralpha2 x CD3 bispecific DART protein for redirected T-cell killing of solid tumors" introduced the IL13Rα2 x CD3 DART molecule that re-targets cytotoxic T cells through its CD3 arm to IL13Rα2 on tumors cells, resulting in the killing of tumor cells. After selection from a range of IL13Rα2 x CD3 DART prototypes, a lead candidate was selected and converted into a humanized, Fc-bearing DART molecule that mediated potent redirected T-cell killing of tumor cells. The study further showed that administration of the Fc-bearing IL13Rα2 x CD3 DART molecule mediated potent anti-tumor activity in vivo in mice reconstituted with human immune cells. Further studies are underway to characterize the molecule as a potential development candidate for the treatment of IL13Rα2-positive cancers.

EphA2 x CD3 DART: MacroGenics has selected EphA2, a receptor tyrosine kinase that plays a critical role in cancer progression, as a potential therapeutic target for a new DART molecule designed to co-engage cytotoxic T cells (via their CD3 component) with EphA2-expressing tumor cells. In the presentation titled "Evaluation of EphA2 as a therapeutic target for redirected T-cell killing by DART bispecific molecules," MacroGenics researchers identified seven anti-EphA2 mAbs recognizing independent epitopes that were engineered into EphA2 x CD3 DART molecules showing a range of potency in redirecting T cells to kill EphA2-expressing target cells. A lead EphA2 x CD3 DART molecule was selected based on potency, engineered into an Fc-bearing DART molecule and shown to mediate target dependent anti-tumor activity in vitro and in vivo. MacroGenics has been encouraged by the results of this study and believes further preclinical assessment studies of EphA2 x CD3 DART molecules are warranted.
Background on DART Platform

MacroGenics’ DART platform enables the targeting of multiple antigens or cells by using a single molecule with an antibody-like structure. DART molecules can be configured for the potential treatment of cancer, autoimmune disorders and infectious diseases. These DART molecules can be tailored for either short or prolonged pharmacokinetics and have demonstrated good stability and attractive manufacturability. Six DART molecules, including programs being developed by MacroGenics and its collaborators, are currently being evaluated in Phase 1 clinical studies.

On April 19, 2016 – Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported new preclinical data demonstrating enhanced systemic anti-tumor activity in preclinical cancer models with intra-tumoral administration of IMO-2125 in combination with an inhibitor of the immunosuppressive enzyme, indoleamine-pyrrole 2,3-dioxygenase (IDO1) (Press release, Idera Pharmaceuticals, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158201 [SID:1234511058]). IMO-2125 is a synthetic oligonucleotide-based agonist of Toll-like receptor 9 discovered and developed by Idera. IDO is one of several immune checkpoints involved in tumor immune escape. IDO-1 inhibitors are currently in clinical development. These data are being presented at the AACR (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, LA.

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"There is an extensive body of evidence which demonstrates that modulating the tumor microenvironment is critical to a successful outcome in cancer immunotherapy", stated Sudhir Agrawal, D.Phil., President of Research at Idera Pharmaceuticals. "In preclinical models, previously we have seen compelling systemic anti-tumor effects with intra-tumoral IMO-2125 monotherapy, in combination with inhibitors of CTLA-4, PD-1, and now, IDO."

In the presentation, entitled "Creating the tumor microenvironment for effective immunotherapy: Anti-tumor activity of intra-tumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO)," Idera scientists presented data further supporting the hypothesis that intra-tumoral IMO-2125 changes the tumor microenvironment by increasing tumor-infiltrating lymphocytes (TILs) and generating a favorable tumor microenvironment. Changes in IDO checkpoint inhibitor expression were also observed.

In the current studies, IMO-2125 (alone and in combination with an IDO-1 inhibitor) increased TIL infiltration and decreased the growth of treated and distant tumors, providing evidence of an enhanced systemic antitumor immune response compared to either agent given alone.

In the study we evaluated the antitumor activity of i.t. IMO-2125 in combination with an IDO1 inhibitor in a murine syngeneic colon carcinoma CT26 model. There was a statistically significant decrease in the growth of both local and distant tumors which was greater for combination therapy than for either IMO-2125 or IDO-1 alone (for lung metastases: combination vs IMO-2125: P = 0.0393; combination vs IDO-1 inhibitor: P = 0.0128).

These results and previous observations with IMO plus anti-CTLA4 and IMO plus PD-1 demonstrate that combination immunotherapy with IMO-2125 has the potential to improve clinical outcomes over currently available anti-CTLA4 and PD-1 inhibitors, and now IDO-1 inhibitors. These presentations are all currently available on Idera’s website at View Source

In partnership with the MD Anderson Cancer Center, the company is currently conducting a Phase 1/2 clinical trial of intra-tumoral IMO-2125 in combination with ipilimumab (CTLA4) for the treatment of pembrolizumab (PD1) treated refractory metastatic melanoma patients. The study has also recently been amended to include an arm studying the combination of IMO-2125 and PD1 in the same patient population.

About Toll-like Receptors and Idera’s Immuno-Oncology Research Program

Toll-like receptors (TLRs) are key components of the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) and, more recently, IDO inhibitors work by targeting mechanisms of adaptive immune resistance. It is believed that intra-tumoral administration of IMO-2125 may potentiate the activity of all of these immunotherapies by creating a more favorable tumor microenvironment that includes increased infiltration by TILs.

Idera’s TLR9 agonist, IMO-2125 has been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown to activate dendritic cells and induce interferon and other cytokines. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In preclinical studies in cancer models, IMO-2125 has shown dose-dependent anti-tumor activity in the injected tumor as well as in distant tumors. Anti-tumor activity is associated with changes in the tumor microenvironment, increased T-cell infiltration, and induction of durable, tumor specific memory. In combination with anti-CTLA4, anti-PD1, and IDO1 inhibitor, IMO-2125 has shown greater anti-tumor activity than with either agent alone. In previously completed clinical trials, subcutaneous administration of IMO-2125 was generally well tolerated in about 80 patients with hepatitis C.

On April 19, 2016 Celsion Corporation (NASDAQ: CLSN), an oncology drug development company, reported that preclinical data for GEN-1 in combination with Avastin and Doxil was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Celsion, APR 19, 2016, View Source [SID:1234511057]). GEN-1 is an IL-12 DNA plasmid vector formulated into a nanoparticle with a non-viral delivery system to cause the sustained local production and secretion of the Interleukin-12 (IL-12) protein loco-regionally to the tumor site. The full poster presentation can be found on Celsion’s website at www.celsion.com.

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The poster, entitled "Interleukin-12 Gene Therapy in Combination with Bevacizumab and PEGylated Liposomal Doxorubicin for Treatment of Disseminated Ovarian Cancer", highlighted results from a preclinical study evaluating GEN-1 combined with Avastin and Doxil in a SKOV3 human cell line implanted into immunocompromised (nude) mice compared to control. The results showed that the combination resulted in a statistically significant reduction of tumor burden of greater than 98% compared to control, and a statistically significant 92% reduction in tumor burden compared to Avastin plus Doxil alone. In contrast, Avastin and GEN-1 produced a 39% and 50% reduction in tumor burden, respectively. The combination of GEN-1 with Avastin and Doxil was well-tolerated with no systemic toxicities.

These preclinical data are consistent with the mechanism of action for GEN-1, which exhibits certain anti-angiogenic properties in addition to its well-characterized immunomodulatory activities.

"These remarkable preclinical results underscore the synergistic activity of GEN-1 and Avastin plus Doxil, with dramatic reductions in tumor volume compared to either therapy alone. The data from this trial, together with the scientific rationale for our approach, reinforce our confidence in the potential of this combination to improve outcomes for patients with platinum-resistant ovarian cancer," said Khursheed Anwer, PhD, executive vice president and chief science officer of Celsion.

The poster also reviews clinical data from a dose-escalation study evaluating GEN-1 plus Doxil in platinum resistant ovarian cancer (the GOG study). In the GOG study, at the highest dose level, GEN-1 plus Doxil produced an objective response rate (ORR) of 29%. This compares favorably to the data from the Phase 3 AURELIA trial in platinum-resistant ovarian cancer, which demonstrated that Avastin plus chemotherapy produced an ORR of 27%. Historical data for trials evaluating Doxil monotherapy in platinum resistant ovarian cancer suggest ORR of only 8% to 12%.

"Our product development strategy for GEN-1 has been reinforced by the recent FDA approval of Avastin as a treatment for platinum-resistant ovarian cancer coupled with our recent clinical results using GEN-1 plus Doxil and three strongly supportive preclinical studies that have consistently shown improved outcomes when GEN-1 is combined with standard of care chemotherapy and Avastin," said Michael H. Tardugno, Celsion’s chairman, president and CEO. "We are now completely focused on evaluating this combination in the clinical setting, and look forward to initiating a Phase I/II trial with the goal of evaluating how the synergistic anti-cancer effects of GEN-1 together with Avastin and Doxil may improve response rates in platinum-resistant ovarian cancer."

The Company is currently enrolling patients in the OVATION Study, a Phase 1b dose escalating trial combining GEN-1 with neo-adjuvant therapies in newly diagnosed ovarian cancer patients, which will provide a starting dose for the follow-on Phase I/II study combining GEN-1 with Avastin and Doxil. The Phase I/II combination trial is expected to begin in fourth quarter of 2016.

About GEN-1 Immunotherapy

GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell activation and proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer, and recently completed a Phase Ib trial of GEN-1 in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer.

On April 19, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), reported updated data from an ongoing Phase I/II clinical trial in refractory glioblastoma multiforme (GBM) with its lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans (Press release, DelMar Pharmaceuticals, APR 19, 2016, View Source [SID:1234511055]).

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In summary, DelMar presented that:

A well-tolerated VAL-083 dosing regimen of 40 mg/m2/daily every 3 days in a 21 day cycle has been selected for advancement into a Phase III refractory GBM study;

The Phase III study design and initiation shall be determined in consultation with the USDFA during a meeting planned for the first half of 2016;

The majority of GBM patients enrolled in DelMar’s Phase I/II clinical trial have tumors exhibiting features correlated with resistance to currently available therapies, aggressive disease and poor patient outcomes; and

This clinical trial is ongoing with expected median survival of eight to nine months following bevacizumab failure. Results to date support the potential of VAL-083 to offer a clinically meaningful survival benefit and a promising new treatment option for GBM patients who have failed or are unlikely to respond to currently available chemotherapeutic regimens.

"We are pleased with the continued progress and promise of VAL-083 as a potential new treatment for GBM," said Jeffrey Bacha, DelMar’s chairman & CEO. "We look forward to discussing our plans for advancement into registration-directed Phase III clinical trials with the USFDA in the coming months."

Abstract #CT074, Phase I/II study of VAL-083 in patients with recurrent glioblastoma, was presented as a late-breaking abstract during the "Phase II/III Clinical Trials in Progress" session.

DelMar’s Phase I/II protocol was designed to establish a safe dosing regimen for VAL-083 in refractory GBM patients before advancing the agent to larger and more advanced clinical studies. Enrolled patients must have recurrent GBM and have failed both temozolomide (TemodarTM) and bevacizumab (AvastinTM) unless one or both are contraindicated.

In studies of VAL-083 conducted by the National Cancer Institute (NCI) in the 1970s and 1980s, a variety of dose regimens were used to treat a range of cancers, including GBM. The most common regimen was 25-30 mg/m2/day for 5 days, with re-treatment every 5 weeks.

DelMar’s dosing regimen uses a cycle of treatment consisting of intravenous VAL-083 administered on days 1, 2 and 3 of a 3-week cycle. The three-day dose regimen was developed to be more patient-friendly than a five-day sequence and to take advantage of a shorter platelet nadir and recovery period observed in the literature.

Tumor Response and Outcomes
GBM patients were not re-resected prior to treatment with VAL-083 and therefore had a growing recurrent GBM tumor at the time of enrollment. Patients were monitored for tumor response by MRI.

Consistent with un-resected refractory GBM, median progression free survival (PFS) was short at 1.2 months (range: 0.2 – 20.1 months). Five GBM patients treated with VAL-083 were reported to have stable disease as their best response following treatment; the remainder reported progressive disease.

Ad-hoc subgroup analysis of the Phase 1 dose-escalation data indicated a dose response trend. Increase survival was observed at 6, 9 and 12 months following initiation of treatment in a high dose (30 and 40mg/m2) sub-group vs. a low dose (≤5mg/m2) sub-group.

GBM patients failing bevacizumab have a poor prognosis with expected survival under five months. To date, more than half of patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) have survived more than six months following bevacizumab failure; more than 40% have survived for nine months or are currently alive and more than 20% have survived for twelve months or are currently alive with median survival expected to be determined at between eight and nine months following bevacizumab failure.

The study is ongoing and analysis of patient outcomes is continuing.

MGMT & IDH1
High expression of DNA repair protein O6-methylguanin-DNA-methyltransferase and wild-type form of the enzyme isocitrate dehydrogenase (IDH1) have been correlated with poor outcomes in GBM. The methylation status of the MGMT promoter was characterized by PCR and/or ELISA for nineteen GBM patients enrolled in DelMar’s trial; IDH1 status was reported in eleven patients; both MGMT and IDH1 status were reported in four patients.

Of patients tested, 84% exhibited high MGMT and 90% were wild-type IDH1. All patients whose samples were tested for both markers were MGMT unmethylated by PCR and wild-type IDH1, a genotype that is correlated with particularly poor prognosis.

These data indicate that the majority of patients enrolled in DelMar’s clinical trial have GBM tumors that exhibit features correlated with resistance to currently available therapies, aggressive disease and poor patient outcomes.

Pharmacokinetics
Pharmacokinetic (PK) analyses showed dose-dependent linear systemic exposure with a short (1-2h) plasma terminal half-life; average Cmax at 40 mg/m2/day was 781 ng/mL (5.3µM). The observed PK profile is comparable to published literature. Prior NCI-sponsored studies demonstrated that VAL-083 readily crosses the blood brain barrier and has a long (>20 hour) half-life in the central nervous system.

Based on observed and previously published pharmacokinetics, DelMar believes that therapeutic doses equal to or above 20 mg/m2 daily on days 1, 2 and 3 of a 21 day cycle should deliver sufficient levels of VAL-083 to brain tumors to achieve a therapeutic benefit.

Safety & Tolerability
In the DelMar Phase I dose escalation regimen, no serious adverse events (SAEs) related to VAL-083 were encountered at doses up to 40 mg/m2/day.

Increasing frequency of and higher grade hematologic toxicities were observed at doses above 40 mg/m2/day. Consistent with the published literature, the observed dose limiting toxicity for VAL-083 is primarily thrombocytopenia. Observed platelet nadir occurred at approximately day 18, and recovery was rapid and spontaneous following treatment.

Based on Phase 1 observations, fourteen additional patients were enrolled in a Phase 2 expansion cohort at 40mg/m2.

Consistent with Phase 1, the dose of VAL-083 40 mg/m2 on days 1, 2 and 3 of a 21 day cycle was generally well tolerated in Phase 2. At this dose, one subject previously treated with CCNU reported Grade 4 thrombocytopenia (low platelets). As a result of this observation, the protocol inclusion criterion for platelet count was increased from 100,000/μL to 150,000/μL for patients receiving prior nitrosoureas within 12 weeks preceding enrollment. No other dose limiting toxicities were observed at this dose.

Next Steps
DelMar plans to discuss a proposed registration-directed Phase III protocol and data from its current Phase I/II clinical trial with the USFDA in the coming months with a goal of advancing VAL-083 into registration-directed clinical trials for GBM patients who have failed temozolomide and bevacizumab. Subject to discussions with USFDA and the Company’s advisors, along with sufficient financial resources, DelMar hopes to initiate a registration-directed Phase III clinical trial with VAL-083 in refractory GBM within the next six to nine months.

In addition to the proposed Phase III clinical trial, DelMar plans to conduct two additional Phase II studies in separate GBM populations:

In collaboration with the University of Texas MD Anderson Cancer Center, DelMar plans to conduct a randomized Phase II clinical trial of VAL-083 versus CCNU in bevacizumab-naïve MGMT-unmethylated GBM patients at first recurrence/progression to confirm the tolerability of DelMar’s dosing regimen and assess outcomes in recurrent bevacizumab-naïve GBM patients whose tumors are known to express high levels of MGMT (clinicaltrials.gov identifier: NCT02717962); and
In collaboration with Sun Yat-Sen University and Guangxi Wuzhou Pharmaceutical (Group) Co., Ltd, DelMar plans to conduct a single arm Phase 2 clinical trial to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy (XRT) and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high levels of MGMT.

"We believe that the results of these planned studies, if favorable, will position VAL-083 to create a paradigm shift for the majority of GBM for patients whose tumors exhibit molecular features that make them unlikely to respond to currently available chemotherapies," stated Mr. Bacha.

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas. DelMar recently announced that the USFDA’s Office of Orphan Products had also granted an orphan designation to VAL-083 for the treatment of medulloblastoma.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar has been conducting a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies. The trial is being conducted at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO) (clinicaltrials.gov identifier: NCT01478178). DelMar announced the completion of enrollment in a Phase II expansion cohort in September, 2015.

About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and most malignant form of brain cancer. Approximately 15,000 people are diagnosed with GBM each year in the U.S., with similar incidence in Europe. Standard of care is surgery, followed by either radiation therapy, or radiation therapy combined with temozolomide. Approximately 60 percent of GBM patients treated with temozolomide experience tumor progression within one year. More than half of glioblastoma patients will fail the currently approved therapies and face a very poor prognosis.

On April 19, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and reported that its collaborators from the University of British Columbia’s Vancouver Prostate Center presented results of new research related to the anti-cancer mechanism of its lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol) (Press release, DelMar Pharmaceuticals, APR 19, 2016, View Source [SID:1234511054]).

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Abstract #2985: "Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment," is being presented during this morning’s "New Mechanisms of Anticancer Drug Action" session at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans.

Specifically,

VAL-083 displayed broad anti-tumor activity against lung and prostate cancer cells;
VAL-083 treatment causes rapid and durable DNA interstrand crosslinks leading to irreparable DNA double-strand breaks, S/G2 phase cell-cycle arrest and apoptosis in cancer cells; and
This new understanding of the molecular mechanisms underlying VAL-083’s anti-cancer activity offers support for effective combination therapies.
"These data indicate that the DNA-damaging cross-links resulting from VAL-083 treatment occur rapidly and, once formed, are not easily repaired by the cell," noted Dr. Dennis Brown, DelMar’s Chief Scientific Officer.

"Typically, a normal cell employs check-point control and DNA repair mechanisms to identify and remove DNA cross-links and double strand breaks such as those resulting from treatment with VAL-083. However, cancer cells, by their very nature tend to have mutations or deficiencies in these mechanisms that may allow VAL-083 mediated cross-links to persist resulting in irreparable and lethal damage to the tumor cell."

Jeffrey Bacha, DelMar’s chairman & CEO continued, "These findings are very exciting and continue to support our belief that VAL-083’s anti-cancer mechanism is unique. Understanding where in the cell cycle VAL-083 elicits its cancer-lethal activity provides guidance in considering combination therapies. This knowledge combined with our own and historical clinical data demonstrating activity against a number of tumors truly establishes a broad stage for the future clinical development of VAL-083."

About the Research:

VAL-083 (dianhydrogalactitol) is a bi-functional alkylating agent causing N7-guanine alkylation and inter-strand DNA crosslinks. VAL-083’s cytotoxic activity is independent of MGMT-expression in various cancer cells and cancer stem cells, suggesting a mechanism that is distinct from that of other alkylating agents. Preclinical and clinical trial data suggest that VAL-083 may have effects in treating various cancers, including lung, brain, cervical, ovarian tumors, and leukemia. However, the detailed molecular mechanisms mediating VAL-083 sensitivity or resistance in cancer have been unclear.

This research was undertaken to investigate the signaling events responsible for VAL-083’s robust activity against cancer.

Crystal violet proliferation assays were performed to assess VAL-083 sensitivity in a variety of cancer cell lines. Propidium iodide (PI) staining and immunofluorescent analyses were used to evaluate cell cycle phases. Western blots were employed to investigate DNA damage response induced by VAL-083 treatment.

Pulse (1 hour) treatment with VAL-083 activated DNA damage signaling pathway as demonstrated by expression of phospho-ATM (S1981), phospho-Chk2 (T68), phospho-RPA32 (S33) and ɣH2A.X which persisted for 24 – 48 hours after removal of VAL-083 from the medium. Specifically, VAL-083 treatment led to long-lasting cell cycle arrest at S/G2 phase of the cell cycle. Additionally, DNA double-strand break signals such as increased levels of ɣH2A.X continued to accumulate at 72 hours following treatment of cancer cells with VAL-083, demonstrating irreparable damage to the tumor cell.

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas. DelMar recently announced that the FDA’s Office of Orphan Products had also granted an orphan designation to VAL-083 for the treatment of medulloblastoma.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar has been conducting a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab (Avastin) and a range of salvage therapies at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

Interim data from the ongoing Phase I/II clinical trial were presented today at the American Association of Cancer Research Annual Meeting (abstract #CT074). Results to date support the potential of a VAL-083 to offer a clinically meaningful survival benefit and a promising new treatment option for GBM patients who have failed or are unlikely to respond to currently available chemotherapeutic regimens. DelMar plans to discuss a proposed Phase III protocol with the FDA in the coming months.