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Chi-Med Initiates a Phase I/II Clinical Trial of Novel FGFR Inhibitor HMPL 453 in China

On June 22, 2017 Hutchison China MediTech Limited (“Chi‑Med”) (AIM/Nasdaq: HCM) reported it has just initiated a Phase I/II clinical trial of HMPL‑453 in China (Press release, Hutchison China MediTech, JUN 22, 2017, http://www.chi-med.com/initiates-ph1-2-of-hmpl-453-in-china/ [SID1234519677]). HMPL‑453 is a novel, highly selective and potent small molecule inhibitor targeting fibroblast growth factor receptor (“FGFR”). The first drug dose was administered on June 19, 2017. This study complements the first-in-human Phase I clinical trial in Australia that was initiated earlier this year.

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This Phase I/II study is a multi‑center, single‑arm, open‑label, two‑stage study to evaluate safety, tolerability, pharmacokinetics (“PK”) and preliminary efficacy of HMPL‑453 monotherapy in patients with solid tumors harboring FGFR genetic alterations. The dose-escalation stage will enroll patients with locally advanced or metastatic solid tumors, for whom standard therapy either does not exist or has proven to be ineffective or intolerable, regardless genetic status, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (“RP2D”).

The dose-escalation will be followed by a dose-expansion stage, which will further evaluate safety, tolerability and PK as well as preliminary anti-tumor efficacy at the RP2D. This stage will enroll primarily cancer patients harboring FGFR dysregulated tumors, including those with advanced bladder cancer, advanced cholangiocarcinoma and other solid tumors. For this second stage, the primary endpoint is objective response rate (ORR), with secondary endpoints including duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT03160833.

About bladder cancer and cholangiocarcinoma
Bladder cancer makes up approximately 90% of urothelial carcinomas. Bladder cancer is the sixth most common cancer in the U.S., and the ninth most common cancer in China, with about 80,000 new cases annually in both countries.[1],[2] In the U.S. the five-year survival rate for those whose disease has metastasized is approximately 5%.[1] Despite advances in the treatment of locally advanced or metastatic urothelial carcinoma, the prognosis for patients remains poor and more treatment options are needed.

A highly unmet medical need around the world, cholangiocarcinoma (bile duct cancer, “CCA”) accounts for approximately 3% of all gastrointestinal cancers and is the most common malignancy of the biliary tract (the combined system of the liver, gall bladder and bile ducts).[3] CCA is classified as intrahepatic or extrahepatic based on anatomical location, with studies suggesting that the incidence of intrahepatic CCA in particular is increasing.[4] Currently CCA has a bleak prognosis, with a 5-year survival rate of less than 5%.[5]

About FGFR
FGFRs are a sub‑family of receptor tyrosine kinases. Activation of FGFR signaling pathways is central to several biological processes. In normal physiology, FGF/FGFR signaling is involved in embryonic development (organogenesis and morphogenesis), tissue repair, angiogenesis, neuroendocrine and metabolism homeostasis. Given its complexity and critical role in a number of important physiological processes, aberrant FGFR signaling has been found to be a driving force in tumor growth, promotion of angiogenesis, as well as conferring resistance to anti‑tumor therapies. To date, there are no approved therapies specifically targeting the FGFR signaling pathway.

About HMPL‑453
HMPL‑453 is a novel, highly selective and potent small molecule inhibitor targeting fibroblast growth factor receptors 1, 2 and 3. In pre‑clinical studies, HMPL‑453 demonstrated superior potency and better kinase selectivity as compared to other drugs in the same class, as well as a favorable safety profile. Chi‑Med is also conducting a Phase I study of HMPL‑453 in Australia, for which additional details can be found at clinicaltrials.gov, using identifier NCT02966171.

Novartis combination targeted therapy Tafinlar® + Mekinist® receives FDA approval for BRAF V600E mutant metastatic non-small cell lung cancer (NSCLC)

On June 22, 2017 Novartis reported the US Food and Drug Administration (FDA) approval of Tafinlar (dabrafenib) in combination with Mekinist (trametinib) to treat patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express the BRAF V600E mutation (Press release, Novartis, JUN 22, 2017, View Source [SID1234519674]). The FDA granted Tafinlar + Mekinist Breakthrough Therapy designation in July 2015 for the treatment of patients with advanced or metastatic BRAF V600E mutation-positive NSCLC who received previous treatment with chemotherapy.

"Patients with BRAF V600E mutation-positive metastatic NSCLC have responded less favorably to standard chemotherapy, suggesting that there is a critical need for a targeted therapy," said Bruno Strigini, CEO, Novartis Oncology. "Today’s approval of the Tafinlar + Mekinist combination validates our expertise in tumor biology, which enabled us to develop the first targeted treatment for people with this rare mutation."

"The approval of Tafinlar + Mekinist makes BRAF V600E the fourth actionable genomic biomarker in metastatic NSCLC – along with EGFR, ALK and ROS-1," said Bruce Johnson, MD, Professor of Medicine, Chief Clinical Research Officer, Dana-Farber Cancer Institute and Harvard Medical School at Dana-Farber Cancer Institute. "This is an important milestone for the lung cancer community as we are continuing to better understand the genomic drivers of cancer and develop effective treatments targeted for these biomarkers."

The FDA approval is based on safety and efficacy of Tafinlar in combination with Mekinist in a Phase II, three-cohort, multicenter, non-randomized, non-comparative and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled (36 treatment-naïve [previously untreated] and 57 previously treated with chemotherapy)[1].

Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 61% (95% confidence interval [CI]: 44%, 77%)[1]. In the previously treated population receiving the same dosage, patients demonstrated an ORR of 63% (95% CI: 49%, 76%)[1]. The ORR was assessed by independent review committee. The median duration of response in the treatment naïve cohort was not estimable (95% CI: 6.9, not estimable) and in the previously treated patient cohort was 12.6 months (95% CI: 5.8, not estimable)[1]. An in-depth analysis of data from the treatment-naïve cohort will be presented at an upcoming medical meeting.

The most common adverse events (incidence >20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough and dyspnea.

BRAF mutations appear in approximately 1-3% of NSCLC cases worldwide[3]. There is an urgency to treat people with this mutation, as BRAF V600E mutation-positive tumors have been shown to be more aggressive and may lead to a poorer prognosis[2].

The treatment combination was approved with Thermo Fisher Scientific’s Oncomine(TM) Dx Target Test to identify a BRAF V600E mutation in eligible patients. This qualitative in vitro diagnostic test uses targeted high throughput, parallel-sequencing technology to detect sequence variations in select genes, including BRAF V600E, in DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using the Ion PGM(TM) Dx System.

Tafinlar + Mekinist was approved by the European Commission (EC) in March 2017 for the treatment of patients with BRAF V600 advanced mutation-positive NSCLC.

Novartis Commitment to Lung Cancer
Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined, and an estimated 1.8 million new cases of lung cancer are diagnosed each year[4],[5]. Among patients with NSCLC, roughly 30% have an actionable mutation that may be targeted with available therapies[6]-[9]. To determine the most appropriate treatment, medical organizations recommend genomic testing for patients with lung cancer[10].

Novartis Oncology’s research in targeted therapies has helped transform treatment approaches for patients living with mutation-driven types of lung cancer. Patients with mutation-driven NSCLC may be candidates for treatment with targeted therapies[6].

Novartis continues its commitment to the global lung cancer community through ongoing studies, as well as the exploration of investigational compounds that target genetic biomarkers in NSCLC.

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600E mutation is approved in the US, EU, Australia, Canada, and additional countries. The combination of Tafinlar and Mekinist is also approved for the treatment of advanced non-small cell lung cancer with a BRAF V600 mutation in Europe.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 50 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600E mutation.

INDICATIONS
TAFINLAR, in combination with MEKINIST, is a prescription medicine used to treat people with a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene.

MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma, and it did not work or is no longer working.

TAFINLAR, in combination with MEKINIST, is a prescription medication used to treat a type of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic NSCLC), and that has a certain type of abnormal "BRAF V600E" gene.

IMPORTANT SAFETY INFORMATION for TAFINLAR (dabrafenib) capsules and MEKINIST (trametinib) tablets
TAFINLAR, in combination with MEKINIST, may cause serious side effects such as the risk of new cancers, including a type of skin cancer called cutaneous squamous cell carcinoma (cuSCC) and a type of skin cancer called basal cell carcinoma. Patients should be advised to contact their doctor immediately for a new wart, skin sore, or bump that bleeds or does not heal, or a change in the size or color of a mole.

TAFINLAR, in combination with MEKINIST, can cause serious bleeding problems, especially in the brain or stomach, and can lead to death. Patients should be advised to call their health care provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," or have red or black stools that look like tar.

TAFINLAR, in combination with MEKINIST, can cause inflammation of the intestines, or tears in the stomach or intestines that can lead to death. Patients should tell their health care provider immediately if they have any of the following symptoms: bleeding (see bleeding problems below); diarrhea (loose stools) or more bowel movements than usual, stomach-area (abdomen) pain or tenderness; fever, and nausea.

TAFINLAR, in combination with MEKINIST, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

TAFINLAR, in combination with MEKINIST, can cause heart problems, including heart failure. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their health care provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

TAFINLAR, in combination with MEKINIST, can cause severe eye problems that can lead to blindness. Patients should be advised to call their health care provider right away if they get: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

TAFINLAR, in combination with MEKINIST, can cause lung or breathing problems. Patients should be advised to tell their health care provider if they have new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Fever is common during treatment with TAFINLAR in combination with MEKINIST, but may also be more serious. Fever may happen often or may be severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their health care provider right away if they get a fever.

Rash and other skin reactions are common serious side effects of TAFINLAR, in combination with MEKINIST. In some cases these rashes and other skin reactions can be severe or serious and may need to be treated in a hospital. Patients should be advised to call their health care provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, or skin redness.

Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR, in combination with MEKINIST. For patients who are diabetic, their health care provider should check their blood sugar levels closely during treatment. Their diabetes medicine may need to be changed. Patients should be advised to tell their health care provider if they have increased thirst, urinate more often than normal, or produce an increased amount of urine.

TAFINLAR, in combination with MEKINIST, may cause healthy red blood cells to break down too early in people with G6PD deficiency. This may lead to a type of anemia called hemolytic anemia, where the body does not have enough healthy red blood cells. Patients should be advised to tell their health care provider if they have yellow skin (jaundice), weakness or dizziness, or shortness of breath.

TAFINLAR, in combination with MEKINIST, can cause new or worsening high blood pressure (hypertension). A patient’s blood pressure should be checked during treatment. Patients should be advised to tell their health care provider if they develop high blood pressure, their blood pressure worsens, or if they have severe headache, lightheadedness, or dizziness.

Common side effects of TAFINLAR, in combination with MEKINIST, in people with melanoma include: fever, nausea, chills, headache, joint aches, cough, diarrhea, rash, vomiting, high blood pressure (hypertension), and swelling of the face, arms, or legs.

Common side effects of TAFINLAR, in combination with MEKINIST, in people with NSCLC include: fever, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, rash, swelling of the face, arms and legs, diarrhea, chills, bleeding, cough, and shortness of breath.

Please see full prescribing information for TAFINLAR and MEKINIST at View Source

Idera Announces FDA Orphan Drug Designation for IMO-2125 for the Treatment of Melanoma

On June 22, 2017 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 that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for IMO-2125, an agonist of endosomal Toll-like receptor (TLR) 9 for the treatment of melanoma Stages IIb to IV (Press release, Idera Pharmaceuticals, JUN 22, 2017, View Source [SID1234519649]).

Idera is currently conducting the Phase 2 portion of the ipilimumab combination arm of a Phase 1/2 clinical trial of intratumoral IMO-2125 in patients with anti-PD-1 refractory metastatic melanoma. The objectives of the current trial are to evaluate IMO-2125’s safety, tolerability and clinical activity. The company expects to complete enrollment of the Phase 2 multicenter trial in the second half of 2017 with overall response rate (ORR) data available in the first quarter of 2018. The company has submitted an abstract to provide an update of clinical data from the ongoing trial at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress being held in September, in Spain.

“The Orphan Drug Designation bestowed by the FDA today, represents another important step in the development of IMO-2125,” stated Joanna Horobin, M.B. Ch.B., Idera’s Chief Medical Officer. “A substantial proportion of patients with metastatic melanoma do not benefit from anti-PD-1 therapy. For these patients, with PD-1 refractory melanoma, ipilimumab offers a modest benefit with an overall response rate of 10-13%1,2. Our goal is to significantly improve on this through the combination of IMO-2125 with ipilimumab. We are increasingly encouraged with the data seen to date and look forward to providing our next clinical data update.”

Idera is also enrolling a second arm in the Phase 1/2 clinical trial in patients with PD-1 refractory melanoma to study the combination of IMO-2125 and pembrolizumab which is currently in the dose escalation phase.

In addition to the above mentioned clinical trial, the company recently initiated a trial of IMO-2125 monotherapy in refractory solid tumors, including PD-1 refractory melanoma.

Orphan Drug Designation is granted by the FDA Office of Orphan Products Development to drugs intended for the treatment of a rare disease or condition that affects fewer than 200,000 people in the United States. This designation provides certain incentives, including eligibility for federal grants, research and development tax credits, waiver of PDUFA filing fees and a seven-year marketing exclusivity period, once the product is approved and as long as orphan drug designation is maintained.

The approval of an orphan drug designation request does not alter the standard regulatory requirements and processes for obtaining marketing approval of an investigational drug. Sponsors must establish safety and efficacy of a compound in the treatment of a disease through adequate and well-controlled studies.

About the Phase 1/2 trial of IMO-2125 in PD-1 Refractory Melanoma
The Phase 1/2 trial of intratumoral IMO-2125 in combination with ipilimumab or pembrolizumab is being conducted in patients who are refractory to anti-PD-1 therapy. The phase 1 portion of the trial was conducted at MD Anderson Cancer Center and the phase 2 portion of the trial is being conducted at multiple clinical sites. In the Phase 1 arms of the trial, four dose levels of IMO-2125 (4, 8, 16 and 32 mg) have been administered intratumorally in one selected lesion at weeks 1, 2, 3, 5, 8 and 11, in combination with the standard dosing regimens of ipilimumab or pembrolizumab, beginning on week 2. The Phase 2 expansion portion of the trial utilizes a Simon two-stage design. If at least 2 of the first 10 patients treated at the Phase 2 dose experience confirmed response the futility hurdle has been met and the trial may continue to enroll. Phase 2 will evaluate 21 patients at the phase 2 dose. Tumor biopsies have been collected pre- and post-24 hours of the first dose of IMO-2125, as well as at 8 and 13 weeks to evaluate multiple immune markers. Clinical activity has been evaluated by the RECIST v1.1 criteria. Clinical data from this study has been presented at SITC (Free SITC Whitepaper) 2017, ASCO (Free ASCO Whitepaper)-SITC 2017 and AACR (Free AACR Whitepaper) 2017, and can be found also on Idera’s corporate website at View Source

About IMO-2125
Toll-like receptors (TLRs) play a central role in 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) are designed to enable the immune system to recognize tumor cells. In this setting, intratumoral TLR9 agonist administration may increase the tumor-infiltrating lymphocytes (TILs), and thereby potentiate anti-cancer activity of checkpoint inhibitors in the injected tumor as well as systemically.

IMO-2125, Idera’s TLR9 agonist, has been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown in various scientific presentations and publications to activate dendritic cells and induce interferon. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In previously completed clinical trials, subcutaneous administration of IMO-2125 was very well tolerated in about 114 patients with hepatitis C. Idera has conducted further preclinical and clinical research evaluating the potential of IMO-2125 to enhance the anti-tumor activity of other checkpoint inhibitors in cancer immunotherapy with data has been presented at several scientific and medical conferences during the past few years. The posters from these presentations can be found at View Source

About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as by through the lymphatic system (metastatic disease). Melanoma accounts for only one percent of skin cancer cases, but causes a large majority of skin cancer deaths. The American Cancer Society estimates that in 2017, there will be 87,110 new cases of melanoma in the U.S., and about 9,730 will die of this disease. Based on proprietary Idera research, the company anticipates by the year 2025, there will be roughly 13,000 anti-PD-1 refractory metastatic melanoma patients.

FDA Approves Genentech’s RITUXAN HYCELA, A Subcutaneous Rituximab Coformulated With Halozyme ENHANZE Technology

On June 22, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported that the U.S. Food and Drug Administration (FDA) has approved Genentech’s RITUXAN HYCELATM, a combination of rituximab and Halozyme’s hyaluronidase human ENHANZE technology, for subcutaneous injection in multiple blood cancer indications (Press release, Halozyme, JUN 22, 2017, View Source [SID1234519648]).

"We are pleased that RITUXAN HYCELA will now provide another treatment option for U.S. patients," said Dr. Helen Torley, president and chief executive officer. "RITUXAN HYCELA has the potential to reduce the treatment burden and administration time, and is an option preferred by many patients."

RITUXAN HYCELA has been approved for patients with follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and is expected to be available within one to two weeks. Including all approved indications, Roche reported total 2016 sales of rituximab in the United States of approximately $3.9 billion. Across all of its global collaboration and licensing agreements, Halozyme earns on average a mid-single-digit royalty on sales of products using the ENHANZE technology.

Today’s approval was preceded by an FDA Oncologic Drug Advisory Committee in March that voted 11 to 0 in favor of the benefit/risk profile for rituximab/human hyaluronidase subcutaneous (under the skin) injection for patients in the proposed indications of follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia.

DelMar Pharmaceuticals Receives Institutional Review Board Approval for Pivotal Phase 3 Clinical Trial of VAL-083 in Refractory GBM

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]).

"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."

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%.