On June 22, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and "the Company"), a biopharmaceutical company focused on the development of new cancer therapies, reported it has received Institutional Review Board (IRB) approval to conduct its pivotal Phase 3 Study in Temozolomide-Avastin (bevacizumab) Recurrent GBM (STAR-3) (Press release, DelMar Pharmaceuticals, JUN 22, 2017, View Source [SID1234519647]). Schedule your 30 min Free 1stOncology Demo! "IRB approval is an essential step in initiating patient enrollment in our Phase 3 trial," stated Jeffrey Bacha DelMar’s chairman & CEO. "We are pleased to remain on track to open enrollment in this trial at leading centers in the United States. Based on our research, we believe that VAL-083 offers significant potential as a new therapy for GBM patients who currently have no viable treatment options."
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Under FDA regulations, Institutions Review Boards (IRBs) are required to review all human subject research to ensure that the rights and welfare of human subjects are protected at all times. To accomplish this purpose, IRBs are comprised of physicians and research administrators with the authority to approve, require modifications to, or disapprove research. The VAL-083 STAR-3 GBM trial and all pertinent study related materials were critically examined by Schulman IRB, the leading independent institutional review board, and approved without any modifications.
About the VAL-083 STAR-3 GBM Trial
DelMar’s VAL-083 STAR-3 GBM trial is an adaptive design, randomized, controlled pivotal Phase 3 clinical trial in patients with glioblastoma multiforme (GBM) whose disease has progressed following prior treatment with temozolomide and bevacizumab.
A total of up to 180 eligible patients will be randomized at approximately 25 centers in the United States to receive either the investigational drug (VAL-083) or "investigator’s choice salvage therapy" as a contemporaneous control, in a 2:1 fashion. Up to 120 eligible patients will be randomized to receive intravenous VAL-083 at 40 mg/m2 on days 1, 2, and 3 of a 21-day treatment cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation. Up to 60 patients will be randomized to "investigator’s choice" control, limited to temozolomide, lomustine, or carboplatin, until they fulfill one of the criteria for study discontinuation.
In both study arms, interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21 days while receiving treatment. Tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study. The study is estimated to last less than two years from initiation.
The primary endpoint of the trial is overall survival. The statistical design between the two arms of the study is 90% power, and is proposed to include an interim analysis at 50% events for futility with O’Brien-Fleming superiority boundary and non-binding, gamma (-5) futility boundary.
About VAL-083
VAL-083 (dianhydrogalactitol) is a "first-in-class", DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institutes.
VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas.
DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details regarding these studies can be found at View Source
DelMar’s recent outcomes in Phase 1-2 clinical trials suggested that VAL-083 may offer a clinically meaningful survival benefit for patients with recurrent GBM following treatment with both TMZ and bevacizumab. A well-tolerated dosing regimen of 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle was selected for study in subsequent GBM clinical trials.
DelMar has embarked human clinical trials for VAL-083 across multiple lines of GBM therapy. These trials include, i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab, improves overall survival, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962); ii) a pivotal, controlled Phase 3 study in temozolomide-Avastin Recurrent GBM ("STAR-3") to evaluate overall survival versus salvage chemotherapy (clinicaltrials.gov identifier: NCT03149575); iii) a single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.
About Glioblastoma Multiforme (GBM)
Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%.
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OSE-172 (Effi-DEM) is a monoclonal antibody: a new generation checkpoint inhibitor which blocks the generation of pro-tumor suppressor cells and restores their effector function.
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OSE-172 blocks SIRP-alpha (Signal Regulatory Protein Alpha), on strategic SIRP-alpha/CD47 pathway, a receptor strongly expressed by myeloid and macrophage suppressor cells. It restores effector functions of these suppressor cells, an activity which promotes the immunosurveillance (Hanna R.N. et al ; Science 2015). OSE-172 may also be combined with other immunotherapies, in particular with checkpoint inhibitors acting on T lymphocytes, e.g. checkpoint inhibitors targeting the PD-1/PD-L1 axis or products triggering a stimulation of the immune system.
This innovative product helps modifying Tumor Associated Macrophages (TAM) and Myeloid Derived Suppressor Cells (MDSC) associated with a poor prognosis, by blocking and transforming them into cells with a good prognosis (in blue in the above diagram).
Proof of concept obtained in in vivo models
Proof of concept has been obtained in models of aggressive cancers such as primary liver cancer, melanoma and breast cancer. These studies have confirmed a therapeutic effect of OSE-172 (Effi-DEM) as well as a potential long-lasting effect, in both monotherapy or combined with another checkpoint inhibitor, or with an immune system stimulator.
The therapeutic effect can be considered as long-lasting as reinsertion of a new tumor in animals treated by OSE-172 shown to be impossible : animals had developed an anti-tumor immunization. A treatment with OSE-172 as a monotherapy and combined with other immunotherapies induces a strong and long-lasting anti-tumor effect.
OSE-172 could be developed in all cancers involving TAM and MDSC cells, key cells in the progression of inflammatory cancers. Cytokines secreted by suppressor cells foster this mechanism (IL-10, IL-1β, TGFβ). This therapeutic strategy could be applied to cancers linked to a chronic inflammation such as primary liver cancer or colon cancer (Zamarron B.F. et 2011) (Mallmann MR et al. 2012).
Rubius Therapeutics Closes $120 Million Financing
On June 21, 2017 Rubius Therapeutics, a biotechnology company pioneering the development of a new class of extraordinarily active and differentiated cell therapies reported that it has raised $120 million in a highly oversubscribed private financing (Press release, Rubius Therapeutics, JUN 21, 2017, View Source [SID1234520731]).
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Rubius has developed the technology to grow, genetically engineer and mature long-circulating red cell therapeutics which will provide transformational clinical benefits to a wide range of patients across multiple therapeutic areas. These allogeneic, off-the-shelf products offer the additional advantage of extended stability and storage to allow for rapid, universal access by the medical community. Proceeds will be used to accelerate the advancement of Rubius’ breakthrough Red-Cell Therapeutics (RCT) product portfolio, to further build out the team and to prepare to enter human clinical trials in 2018. This financing follows the successful achievement of several key milestones, including the clinical scale production of cultured red cells in bioreactors and the generation of preclinical proof-of-concept data for several lead programs.
"With this financing, Rubius is well positioned to focus on the continued development of our platform to advance a broad range of therapeutic candidates that have the potential to make a significant difference in the lives of patients," said Torben Straight Nissen, Ph.D., President of Rubius Therapeutics.
"Rubius has achieved multiple scientific and manufacturing milestones in the first six months of this year. Those achievements plus the trust that Flagship and our new investors have put in Rubius with this financing sets us up to turn our RCTs into important new treatment options," said David Epstein, Chairman of Rubius Therapeutics and Executive Partner of Flagship Pioneering.
The RCT platform allows Rubius to express enzymes, agonists, antagonists, binders and combinations in their natural conformation on or inside of red cells. Lead RCT programs include enzyme replacement therapies as well as therapies targeting solid tumors and hematological cancers. Further, Rubius has demonstrated that RCTs provide potential applications across additional therapeutic areas, such as autoimmune disease, infectious disease, metabolic disease and rare diseases, including hemophilia.
"We are excited to expand our support of Rubius in this next round of funding as the company continues to advance its technology and programs — following in the footsteps of Flagship’s family of successful multiproduct platform companies," said Noubar Afeyan, CEO of Flagship Pioneering and Co-Founder of Rubius. "The team at Rubius has made great strides over the past three years and we are pleased to support the company’s continued growth. This new financing, together with a leadership team with unparalleled expertise, positions Rubius to deliver on the promise of the RCT platform and bring transformative therapies to patients."
Rubius was conceived, launched and funded by Flagship VentureLabs, the innovation foundry of Flagship Pioneering. Joined by undisclosed large institutional investors, Flagship Pioneering significantly increased its investment in this financing.
About Red-Cell Therapeutics Red-Cell Therapeutics are genetically engineered, enucleated red cells that provide allogeneic, off-the-shelf therapies to patients across multiple therapeutic areas. RCT advantages over other therapies include immuno-privileged presentation of proteins within or on the red cell, high target avidity and affinity resulting in highly potent and selective therapies, and long circulation half-life. Rubius RCTs exhibit fundamentally unique biology and have been engineered to replace missing enzymes for patients living with a variety of rare diseases, to kill tumors, and upregulate or downregulate the immune system to treat both cancer and autoimmune disorders.
About Rubius Therapeutics Rubius Therapeutics is developing Red-Cell Therapeutics (RCTs) as a new class of medicines to address a wide array of indications, with leading applications in cancer, rare and autoimmune disease, as well as additional potential in hemophilia, infectious and metabolic diseases. The company was founded and launched in 2014 by Flagship VentureLabs, the innovation foundry of Flagship Pioneering. Rubius has successfully engineered and manufactured red cells that express therapeutic proteins for use in the treatment of serious diseases. The company is now demonstrating that these newly equipped high performing, off-the-shelf Red-Cell Therapeutics have pre-clinical activity across a spectrum of medical applications. Rubius has generated more than 200 prototypes to date.
OncoArendi Therapeutics Announces Selection of Its Second Clinical Development Candidate: OATD-02 For the Treatment of Multiple Cancers
On June 21, 2017 / B3C newswire / — During the first Company Presentation at the global BIO Conference in San Diego OncoArendi Therapeutics SA reported that it has selected OATD‑02 as its clinical development candidate for cancer immunotherapy. Submission of the Company’s second Investigational New Drug (“IND”) application is expected by the third quarter of 2018.
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OATD-02 is a highly potent and selective small molecule inhibitor of two arginase isoforms (Arg-1 and Arg-2) in both biochemical and cell-based-assays. OATD-02 is the second arginase inhibitor to enter development.
OATD-02 has been shown to be effective in vivo in three different mouse models of cancer (colorectal, lung and melanoma) and demonstrated superior antitumor efficacy in combinations with the PD-L1 checkpoint inhibitor and with gemcitabine; resulting in a controlled tumor growth, and, in some cases in a full regression.
Pilot studies also suggested a therapeutic potential of OATD-02 in glioblastoma multiforme (GBM), the most malignant brain tumor with no effective treatment.
“We believe that small molecule drugs preventing cancer cells from escaping from the immune surveillance have great potential in combination therapies and to be transformational medicines in the treatment of many types of cancer. The increasing number of clinical trials with multiple IDO inhibitors and various check-point inhibitor combinations additionally validate this approach. At OncoArendi, we are dedicated to research and development of the first-in-class or best-in-class small molecule-based therapies that in combination with other modalities, could significantly improve the treatment of unmet medical needs in many solid and hematopoietic cancers ” said Marcin Szumowski, PhD, CEO of OncoArendi Therapeutics. “We are particularly excited about the potential of arginase as an additional new target in cancer immunotherapy and the potential of OATD-02 to become the best-in-class arginase inhibitor on the market. This compound demonstrated a potent extracellular and cellular activity while its pharmacological profile makes it suitable for oral dosing.”
Formal pre-clinical development of OATD-02 will be initiated next month with GLP toxicology studies expected in Q4 of this year and first in human studies anticipated in the third quarter of 2018. OncoArendi Therapeutics’ arginase inhibitors, including OATD-02, are protected by two pending patents covering two structurally different groups of compounds.
About Arginase Science
Arginase has been recently validated as a promising target in immuno-oncology. Arginase is an enzyme that catalyzes the final step in the urea cycle, during which the body disposes of harmful ammonia. However, in cancer, arginase through its capacity to decrease arginine levels, blocks the natural antitumor immunity by suppressing activation and proliferation of T cells. Even a moderate decrease of arginine levels is immunosuppressive. T-cells deprived of arginine do not die – they retain the ability to expand when arginine is replenished. Since the majority of human cancers exhibit a highly increased arginase activity and decreased plasma arginine levels, arginase inhibitors are expected to exhibit a wide clinical utility, in particular in combinations with other therapeutic modalities, such as checkpoints inhibitors and immunogenic therapies.
With a decade-long expertise in the type of chemistry required to synthesize and optimize arginase inhibitors, promising initial data and a strong development team, OncoArendi has laid out a clear strategy to bring to the clinic the best in class arginase inhibitor.
Adaptive Biotechnologies Announces a Collaboration with Janssen Biotech, Inc. to use the clonoSEQ® Assay to Measure Minimal Residual Disease in Ongoing and Future DARZALEX® Multiple Myeloma Trials
On June 21, 2017 Adaptive Biotechnologies, the leader in combining Next Generation Sequencing (NGS) and expert bioinformatics to profile T- and B-cell receptors of the adaptive immune system, reported it has partnered with Janssen Biotech, Inc. to utilize Adaptive’s NGS-based clonoSEQ Assay for measuring minimal residual disease (MRD) in patients with Multiple Myeloma (MM) who have been treated with DARZALEX (daratumumab) (Press release, Adaptive Biotechnologies, JUN 21, 2017, View Source [SID1234519651]). DARZALEX is a CD38-directed cytolytic antibody approved for the treatment of patients with relapsed or refractory MM. Under the terms of the collaboration, Adaptive will receive an undisclosed upfront technology access payment in addition to development funding and potential future milestone payments. Adaptive will be responsible for seeking regulatory approvals for and commercialization of the clonoSEQ Assay in MM. Schedule your 30 min Free 1stOncology Demo! "Adaptive is thrilled to develop the technology to help measure the depth of response generated by DARZALEX in patients with MM," said Chad Robins, CEO and co-founder of Adaptive Biotechnologies. "We look forward to advancing our strategic partnership with Janssen by incorporating the highly sensitive and quantitative clonoSEQ Assay into more trials with DARZALEX."
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Through this collaboration, the parties will work together to demonstrate the clinical utility of monitoring MRD negativity by the clonoSEQ Assay in MM patients who have been treated with DARZALEX, and to assess the medication’s ability to achieve MRD.
"Incorporating novel, proven molecular diagnostic tools into drug development and regulatory processes can enable clinicians to treat patients with the optimal interventions at the right time," said Charles Sang, Adaptive’s Senior Vice President, Diagnostics. "Adaptive’s clonoSEQ Assay can help accomplish this goal due to the robust validation of the assay. We believe the shared commitment of both companies to monitor MRD negativity in patients with MM will drive the success of this collaboration."
About Minimal/Measurable Residual Disease
Minimal/measurable residual disease (MRD) refers to cancer cells that remain in the body of a person with lymphoid cancer after treatment. These cells can be present at levels undetectable by traditional morphologic, microscopic examination of blood, bone marrow or a lymph node biopsy. Sensitive molecular technologies, such as next-generation sequencing utilized by the Adaptive Biotechnologies clonoSEQ Assay, are needed for reliable detection of MRD at levels below the limits of traditional assessment.
About the clonoSEQ Assay
The Adaptive Biotechnologies clonoSEQ Assay enables physicians to utilize next-generation sequencing-based minimal/measureable residual disease (MRD) detection to inform clinical decision making for patients with lymphoid malignancies. The clonoSEQ Assay detects and quantifies DNA sequences found in malignant cells which can be tracked throughout treatment. This robust assay provides consistent, accurate measurement of disease burden which potentially allows physicians to monitor response to treatment over time to optimize patient management. Adaptive will be seeking marketing authorization from the FDA for the clonoSEQ Assay.