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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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%.

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).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On April 19, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported results of three preclinical studies of CPI-444, the Company’s lead oral checkpoint inhibitor (Press release, Corvus Pharmaceuticals, APR 19, 2016, View Source;p=irol-newsArticle&ID=2158492 [SID:1234512141]). The studies demonstrated that CPI-444, a selective and potent inhibitor of the adenosine A2A receptor, was effective in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth and delaying tumor progression in animal models of cancer. The data were presented in oral and poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These preclinical studies demonstrate that CPI-444 enhances the immune response to various tumors in animal models of melanoma, breast and colon cancer. Enhancement of T-cell function was also corroborated with adoptively transferred T-cells and with tumor vaccines, indicating that this agent may have broad applications in immuno-oncology," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "These studies support our commitment to advancing the clinical development of CPI-444 as an immuno-oncology therapy for many types of cancer. Based on these study findings and others, we have begun enrolling patients in a Phase 1/1b clinical trial to evaluate the safety, tolerability and preliminary efficacy of CPI-444 as a single agent and in combination with an anti-PD-L1 in patients with solid tumors."

The Adenosine A2A Receptor Antagonist, CPI-444, Blocks Adenosine-Mediated T-Cell Suppression and Exhibits Anti-Tumor Activity Alone and in Combination with Anti-PD-1 and Anti-PD-L1 (abstract #2337)
Data from this preclinical study were presented in a poster session by Stephen Willingham, Ph.D., senior scientist at Corvus Pharmaceuticals. Results showed that CPI-444 restored T-cell activation in vitro in T-cells that were treated with immuno-suppressive levels of adenosine. CPI-444 demonstrated single-agent anti-tumor activity and synergized with either anti-PD-1 or anti-PD-L1 in multiple animal tumor models, resulting in a significant number of cured animals. CPI-444 combined with anti-PD-L1 treatment resulted in increased CD8+ T-cell infiltrates in tumors, indicating a heightened anti-tumor immune response. In tumor-bearing mice cured by treatment with CPI-444, long-term anti-tumor immunity was demonstrated by showing that all these mice were protected from tumor re-challenge.

Inhibition of Adenosine A2A Receptor (A2AR) by CPI-444 Enhances CD8+ T-Cell Killing of a HER-2/neu Expressing Murine Tumor (abstract #320)
Data from this preclinical study were presented by Blake Scott, a member of the lab of Elizabeth Jaffee, M.D., in The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Jaffee also is associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Results showed that CPI-444 enhanced the activity of adoptively transferred, cancer-specific CD8+ T-cells when administered with a T-cell-inducing tumor vaccine.

Adenosine A2A Receptor (A2AR) Antagonist as a Means of Enhancing the Efficacy of Checkpoint Blockade and Adoptive T-Cell Therapy (abstract #4364)
Data from this preclinical study were presented in an oral session by Robert D. Leone, M.D., Ph.D., of The Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University School of Medicine. Treatment of animals with CPI-444 enhanced tumor immunity by lowering the expression of other inhibitory checkpoint receptors on tumor infiltrating immune cells (e.g., Lag 3, Tim 3 and PD-1). CPI-444 also enhanced the efficacy of adoptively transferred T-cells, leading to suppressed tumor growth and increased survival compared with controls. CPI-444 increased the expansion of antigen-specific T-cells in vitro and synergized with anti-PD-1 antibody treatment and glutamine metabolism inhibitors in animal models of colon tumors. A co-author of the study is Jonathan Powell, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

ABOUT ADENOSINE A2A RECEPTOR ANTAGONISTS
Over the last several years, significant progress has been made in developing immunotherapies for the treatment of cancer, in part due to the development of checkpoint inhibitors — antibodies that block immuno-suppressive mechanisms.

Tumors evade immune attack by usurping pathways that negatively regulate immune responses. Adenosine in the tumor microenvironment leads to the activation of the A2A receptor and has been shown to represent one such negative immune regulatory mechanism. Because the tumor microenvironment produces relatively high concentrations of adenosine, blocking A2A receptor activation has the potential to enhance anti-tumor immunity. Data have demonstrated the ability of A2A receptor blockade to enhance anti-tumor immunity, checkpoint blockade and adoptive T-cell therapy. Studies to date support the development of A2A receptor antagonists as novel immunotherapy treatments.

ABOUT CPI-444
CPI-444, Corvus’s lead checkpoint inhibitor, is an adenosine A2A receptor antagonist. It is designed to disable a tumor’s ability to subvert attack by the immune system by inhibiting adenosine in the tumor microenvironment. CPI-444 is a small molecule that is taken orally. It is in development as an immuno-oncology therapy for the treatment of patients with solid tumors.

Corvus is currently evaluating CPI-444 in a multicenter Phase 1/1b clinical trial in patients with various solid tumors. This successive expansion cohort trial is examining the activity of CPI-444 both as a single agent and in combination with atezolizumab (MPDL3280A), Genentech’s investigational cancer immunotherapy. Atezolizumab is a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PDL-1). Corvus is conducting the trial with Genentech, a member of the Roche Group, under a clinical trial collaboration the two companies entered into in October 2015.

The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations–misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Therapeutic antibody-drug conjugates (ADCs) harness the cell-killing potential of cytotoxic agents and the tumor targeting specificity of monoclonal antibodies to selectively kill tumor cells. Recent years have witnessed the development of several promising modalities that follow the same basic principles of ADC based therapies but which employ unique cytotoxic agents and conjugation strategies in order to realize therapeutic benefit. The complexity and heterogeneity of ADCs present a challenge to some of the conventional analytical methods that industry has relied upon for biologics characterization. This current review will highlight some of the more recent methodological approaches in mass spectrometry that have bridged the gap that is created when conventional analytical techniques provide an incomplete picture of ADC product quality. Specifically, we will discuss mass spectrometric approaches that preserve and/or capture information about the native structure of ADCs and provide unique insights into the higher order structure (HOS) of these therapeutic molecules.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!