Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel.
In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS).
One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings.
Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.
© 2015 by American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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Iomab-B for Hematopoietic Stem Cells Transplantation:

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Iomab-B (BC8-I-131 construct) has already been successfully used as a myeloconditioning/myeloablative agent in over 250 patients with incurable blood cancers (Company Pipeline, Actinium Pharmaceuticals, APR 19, 2016, View Source [SID:1234511053]). In both Phase I and Phase II trials Iomab-B has led to effective cures in patients with no options left. The only potentially curative treatment option for those patients is bone marrow transplantation (BMT), also known as a hematopoietic stem cell transplant (HSCT), but vast majority of patients over the age of 50 are either ineligible for myeloablative conditioning due to concomitant conditions or have a high burden and/or very resistant disease that makes reduced dose conditioning futile.

BC8-I-131 has demonstrated ability to successfully prepare such patients for bone marrow transplants when no other treatment was indicated. ATNM intends to develop Iomab-B through a regulatory approval via a pivotal registration trial in AML refractory/relapsing patients. That would allow for a relatively quick path to the market and provide a potentially curative treatment to patients who currently have little or no chance of achieving even a temporary remission, let alone a cure.

The targeting part of the Iomab-B construct is a monoclonal antibody that targets CD45, an antigen widely expressed on hematopoietic cells but not other tissues. Due to this broad expression, Iomab-B has demonstrated utility in other groups of patients and other indications as well, including Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, Hodgkin’s Disease and Non-Hodgkin Lymphoma. These are follow-on indications which could be pursued simultaneously or delayed, for cash conservation, and financed from commercial revenues.

The company is already preparing a program for replacing iodine 131 with Actinium 225 to create a second generation drug that would enable a significant expansion of use, described below as Actimab-B, Iomab-B was invented by researchers at the Fred Hutchinson Cancer Research Center (FHCRC), ATNM’s key collaborator on this program from whom ATNM obtained rights for all the commercial uses. FHCRC played a pivotal role in developing the entire field of bone marrow transplantation and the lead Hutchinson researcher, Dr. E. Donnall Thomas received the 1990 Nobel Prize in physiology/medicine for work in this area.

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%.

The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor – KDR) and the mouse (fetal liver kinase 1 – Flk-1) receptors. The purified phospholipid-PEG-peptide isolated from TFA-based eluents is not stable with respect to hydrolysis of the fatty ester moieties. This leads to the time-dependent formation of the lysophospholipid and the phosphoglycerylamide derived from the degradation of the product. Purification of the product using neutral eluent systems provides a stable product. Methods to prepare the lysophospholipid (hydrolysis product) are also included. Biacore binding data demonstrated the retention of binding of the lipopeptide to the KDR receptor. The phospholipid-PEG2000-peptide is smoothly incorporated into gas-filled microbubbles and provides imaging of angiogenesis in a rat tumor model.

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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.