On January 13, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company") reported that it has entered into a collaboration with the University of Texas MD Anderson Cancer Center (MD Anderson) to accelerate the clinical development of DelMar’s lead anti-cancer candidate, VAL-083, for the treatment of glioblastoma multiforme (GBM), the most common and deadly form of brain cancer (Press release, DelMar Pharmaceuticals, JAN 13, 2016, View Source [SID:1234508783]). Schedule your 30 min Free 1stOncology Demo! As part of the collaboration, MD Anderson will initiate a new Phase II clinical study with VAL-083 in patients with GBM at first recurrence/progression, prior to Avastin (bevacizumab) exposure. Patients eligible for the study will have recurrent GBM characterized by a high expression of MGMT, the DNA repair enzyme implicated in drug-resistance and poor patient outcomes following current front-line chemotherapy. MGMT promoter methylation status will be used as a validated biomarker for enrollment and tumors must exhibit an unmethylated MGMT promoter for patients to be eligible for the trial.
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VAL-083 is a first-in-class small molecule chemotherapy that readily crosses the blood brain barrier. DelMar’s research has demonstrated that VAL-083’s anti-cancer mechanism is active independent of tumor MGMT status. Approximately 2/3 of GBM patients have tumors with an unmethylated MGMT promoter, which is correlated with resistance to currently available chemotherapy and poor patient outcomes.
"The progress we continue to make with our research shows that VAL-083 may offer advantages over currently available chemotherapies in a number of tumor types," stated Jeffrey Bacha, DelMar’s chairman & CEO. "This collaboration will allow us to leverage world-class clinical and research expertise and a large patient population from MD Anderson as we extend and accelerate our clinical focus to include GBM patients following first recurrence of their disease."
DelMar recently presented favorable interim data at the 2015 Society for Neuro-Oncology Annual Meeting from its ongoing Phase II clinical trial with VAL-083 as a potential "third-line" therapy in GBM patients whose tumors have recurred following treatment with both temozolomide and bevacizumab.
From MD Anderson, the collaboration will be led by Dr. Barbara Jane O’Brien Assistant Professor, Department of Neuro-Oncology, and Marta Penas-Prado, Assistant Professor, Department of Neuro-Oncology,
"We believe that VAL-083’s unique cytotoxic mechanism offers promise for GBM patients across the continuum of care as a potential superior alternative to currently available cytotoxic chemotherapies, especially for patients whose tumors exhibit a high-expression of MGMT," added Mr. Bacha.
DelMar also plans to continue ongoing pre-clinical research related to VAL-083’s unique mechanism of action with researchers at MD Anderson. DelMar has recently presented data stemming from this research at scientific meetings that suggest that VAL-083 may offer new treatment options for GBM, non-small cell lung cancer, ovarian cancer and pediatric medulloblastoma.
"We look forward to working with the world-class scientists and clinicians at MD Anderson to accelerate our research bringing us closer to our vision to transform the treatment of patients whose cancers fail or are unlikely to respond to currently available treatments," 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.
VAL-083 is a bi-functional DNA N7 cross-linking agent that crosses the blood-brain barrier that has demonstrated historical clinical activity against a range of cancers, including GBM, in prior NCI-sponsored clinical trials. DelMar has demonstrated that VAL-083 induces phosphorylation of H2AX, a hallmark of double-strand DNA breaks, leading to cell cycle arrest in the late G2/S phase. H2AX is a histone involved in the CHK2 checkpoint activation pathway, a key component of the body’s immune response to DNA damage that activates down-stream signaling ultimately resulting in apoptosis (cancer cell death). Additionally, the cytotoxic activity of VAL-083 appears to be less dependent on wild type p53 in comparison to other chemotherapeutic agents. Alteration in p53 has been correlated with poor patient outcomes in GBM. In particular, gain-of-function mutant p53 is strongly associated with a poor prognosis for overall survival in patients with glioblastoma, potentially by increasing expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance to temozolomide and poor outcomes in GBM patients.
DelMar has previously demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT. Taken together with historical and recently demonstrated clinical activity, these data suggest a distinct anti-cancer mechanism for VAL-083 which has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM.
DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled 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).
In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.
Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.
Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.
Year: 2016
FORMA THERAPEUTICS ENROLLS FIRST PATIENT IN PHASE 1 STUDY OF FT-1101 IN ADVANCED HEMATOLOGICAL MALIGNANCIES
On January 12, 2016 FORMA Therapeutics reported the initiation of a Phase 1 study of FT-1101, with the first dose administration in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (Press release, Forma Therapeutics, JAN 12, 2016, View Source [SID:1234511394]). FT-1101 is an oral, structurally distinct and potent pan-inhibitor of the BET (Bromodomain and Extra-Terminal) epigenetic protein family.
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"I am impressed with the inhibition profile and differentiated preclinical activity of FT-1101, and we aim to move quickly to define the safety, tolerability and initial activity of this novel BET inhibitor in acute leukemias and myelodysplastic syndrome"
"The BET protein family represents an attractive group of therapeutic targets for a variety of liquid and solid tumors, as inhibition of these epigenetic binding proteins allows for selective effects on gene expression. FT-1101 is a novel, oral small molecule targeted against all four BET family members (BRD2, BRD3, BRD4, BRDT)," said John Hohneker, M.D., EVP and Head of Research and Development, FORMA Therapeutics. "The launch of this study is an important step for our team, and we are eager to begin the selection of preferred dosing schedules and potential patient populations in order to optimize activity and tolerability of this novel medicine."
Small molecule inhibition of BET results in down-regulation of the critical oncogene MYC, a master regulator of diverse cell functions critical for cell growth and survival in many cancers. At tolerated doses in human tumor xenograft mouse models, FT-1101 has demonstrated significant anti-tumor activity including tumor regressions.
FT-1101 is part of FORMA’s second global strategic collaboration with Celgene Corporation announced in April 2014. Celgene has obtained an exclusive EU license for FT-1101 in exchange for an undisclosed payment to FORMA. Under the terms of the collaboration agreement, FORMA will advance the FT-1101 program through Phase 1, and Celgene will be responsible to fund and execute further global clinical development.
"I am impressed with the inhibition profile and differentiated preclinical activity of FT-1101, and we aim to move quickly to define the safety, tolerability and initial activity of this novel BET inhibitor in acute leukemias and myelodysplastic syndrome," said Guillermo Garcia-Manero, M.D., lead clinical investigator for FT-1101 at The University of Texas MD Anderson Cancer Center, Houston, TX, and Professor, Department of Leukemia, Division of Cancer Medicine.
About the Study
The Phase 1 multicenter, open-label, dose escalation clinical trial is designed to assess the safety and tolerability of FT-1101 capsules as a single agent. FT-1101 will be administered orally on a once weekly dosing schedule in a 28-day cycle. The study will enroll patients with relapsed refractory AML and high risk myelodysplastic syndrome. Key objectives in the study include determination of a maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of FT-1101. Please refer to www.clinicaltrials.gov for additional clinical trial details.
About BET
The Bromodomain and Extra-Terminal (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) regulate chromatin structure and gene expression through their ability to bind to acetylated lysine residues on histone tails and act as epigenetic readers. In particular, BRD4 has been shown to positively regulate the expression of MYC and other critical cancer-associated genes through the localization of BRD4 to super-enhancer regulatory elements. Preclinical studies conducted using BET inhibitors and emerging data from ongoing clinical trials in leukemia and lymphoma patients, have provided initial support for the therapeutic potential of BET inhibitors in hematologic malignancies.
FORMA THERAPEUTICS ENROLLS FIRST PATIENT IN PHASE 1 STUDY OF FT-1101 IN ADVANCED HEMATOLOGICAL MALIGNANCIES
On January 12, 2016 FORMA Therapeutics report the initiation of a Phase 1 study of FT-1101, with the first dose administration in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (Press release, Forma Therapeutics, JAN 12, 2016, View Source [SID:1234509342]). FT-1101 is an oral, structurally distinct and potent pan-inhibitor of the BET (Bromodomain and Extra-Terminal) epigenetic protein family.
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!
"I am impressed with the inhibition profile and differentiated preclinical activity of FT-1101, and we aim to move quickly to define the safety, tolerability and initial activity of this novel BET inhibitor in acute leukemias and myelodysplastic syndrome"
"The BET protein family represents an attractive group of therapeutic targets for a variety of liquid and solid tumors, as inhibition of these epigenetic binding proteins allows for selective effects on gene expression. FT-1101 is a novel, oral small molecule targeted against all four BET family members (BRD2, BRD3, BRD4, BRDT)," said John Hohneker, M.D., EVP and Head of Research and Development, FORMA Therapeutics. "The launch of this study is an important step for our team, and we are eager to begin the selection of preferred dosing schedules and potential patient populations in order to optimize activity and tolerability of this novel medicine."
Small molecule inhibition of BET results in down-regulation of the critical oncogene MYC, a master regulator of diverse cell functions critical for cell growth and survival in many cancers. At tolerated doses in human tumor xenograft mouse models, FT-1101 has demonstrated significant anti-tumor activity including tumor regressions.
FT-1101 is part of FORMA’s second global strategic collaboration with Celgene Corporation announced in April 2014. Celgene has obtained an exclusive EU license for FT-1101 in exchange for an undisclosed payment to FORMA. Under the terms of the collaboration agreement, FORMA will advance the FT-1101 program through Phase 1, and Celgene will be responsible to fund and execute further global clinical development.
"I am impressed with the inhibition profile and differentiated preclinical activity of FT-1101, and we aim to move quickly to define the safety, tolerability and initial activity of this novel BET inhibitor in acute leukemias and myelodysplastic syndrome," said Guillermo Garcia-Manero, M.D., lead clinical investigator for FT-1101 at The University of Texas MD Anderson Cancer Center, Houston, TX, and Professor, Department of Leukemia, Division of Cancer Medicine.
FORMA THERAPEUTICS AND CANCER RESEARCH TECHNOLOGY FORM A THIRD VIRTUAL COMPANY TO ADVANCE DEUBIQUITINATION ASSETS
On January 11, 2016 FORMA Therapeutics and Cancer Research Technology, reported the formation of a third new virtual Asset Discovery and Development Company (ADDCos) with novel chemical matter targeting an undisclosed deubiquitinating enzyme (DUB) (Press release, Forma Therapeutics, JAN 12, 2016, View Source [SID:1234509341]). ADDCos are virtual companies that rapidly advance drug discovery innovations in a compelling scientific area through the collaboration of academic thought leaders, FORMA drug discovery scientists and a world class development network.
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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
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This achievement is the result of an ongoing long-term initiative between FORMA and Cancer Research Technology, the commercial arm of Cancer Research UK, to discover innovative tools, technologies and therapeutic drug candidates against a variety of DUBs that regulate protein homeostasis. Under the agreement, FORMA is pairing its ultra-efficient drug discovery and early development capabilities with expertise from Cancer Research Technology’s Discovery Laboratories and the exclusive world-class academic network of Cancer Research UK scientists.
Protein ubiquitination, a highly regulated cellular process controlled in part by DUBs to maintain protein homeostasis with appropriate protein levels and function, contributes to a large number of wide-ranging human diseases when aberrantly dysregulated. DUBs, as members of diverse protein complexes, are key regulators of ubiquitin recycling, processing, proofreading and disassembly. DUBs contain a catalytic domain surrounded by one or more accessory domains, some of which contribute to target recognition, and collectively represent molecular features ideally suited for therapeutic intervention.
"DUBs continue to represent highly attractive discovery targets warranting further exploration," stated Steven Tregay, Ph.D., President and CEO, FORMA Therapeutics. "The evolution of R&D across a distributed network of diverse scientific disciplines allows FORMA to rapidly and creatively advance research discoveries into clinical candidates."
Keith Blundy, CEO of Cancer Research Technology, said: "This partnership has proven to yield exciting biology and translational outcomes, when pairing complementary skills and capabilities together within a unique business structure. We look forward seeing such research discoveries develop into new medicines offering breakthrough treatments to cancer patients worldwide."
FORMA Therapeutics and CRT form a third virtual company to advance deubiquitination assets
On January 12, 2016 FORMA Therapeutics and Cancer Research Technology reported the formation of a third new virtual Asset Discovery and Development Company (ADDCos) with novel chemical matter targeting an undisclosed deubiquitinating enzyme (DUB) (Press release, Cancer Research Technology, DEC 12, 2016, View Source [SID1234523189]). ADDCos are virtual companies that rapidly advance drug discovery innovations in a compelling scientific area through the collaboration of academic thought leaders, FORMA drug discovery scientists and a world class development network.
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!
This achievement is the result of an ongoing long-term initiative between FORMA and Cancer Research Technology, the commercial arm of Cancer Research UK, to discover innovative tools, technologies and therapeutic drug candidates against a variety of DUBs that regulate protein homeostasis. Under the agreement, FORMA is pairing its ultra-efficient drug discovery and early development capabilities with expertise from Cancer Research Technology’s Discovery Laboratories (CRT-DL) and the exclusive world-class academic network of Cancer Research UK scientists.
Protein ubiquitination, a highly regulated cellular process controlled in part by DUBs to maintain protein homeostasis with appropriate protein levels and function, contributes to a large number of wide-ranging human diseases when dysregulated. DUBs, as members of diverse protein complexes, are key regulators of ubiquitin recycling, processing, proofreading and disassembly. DUBs contain a catalytic domain surrounded by one or more accessory domains, some of which contribute to target recognition, and collectively represent molecular features ideally suited for therapeutic intervention.
"DUBs continue to represent highly attractive discovery targets warranting further exploration," stated Steven Tregay, Ph.D., President and CEO, FORMA Therapeutics. "The evolution of R&D across a distributed network of diverse scientific disciplines allows FORMA to rapidly and creatively advance research discoveries into clinical candidates."
Keith Blundy, CEO of Cancer Research Technology, said: "This partnership has proven to yield exciting biology and translational outcomes, when pairing complementary skills and capabilities together within a unique business structure. We look forward seeing such research discoveries develop into new medicines offering breakthrough treatments to cancer patients worldwide."