On June 6, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) and Roivant Sciences Ltd. reported the formation of Myovant Sciences Ltd. ("Myovant"), a biopharmaceutical company focused on delivering innovative women’s health and prostate cancer solutions by efficiently advancing new medicines to market that have the potential to improve the lives of millions of patients (Press release, Takeda, JUN 6, 2016, View Source [SID:1234513109]). In addition, Lynn Seely, MD, an endocrinologist who led the development of XTANDI (enzalutamide) for the treatment of prostate cancer as the Chief Medical Officer of Medivation from 2005 to 2015, was named the President & Chief Executive Officer of Myovant Sciences, Inc.

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!

Myovant Partnership Summary
Takeda has granted Myovant an exclusive, worldwide license (excluding Japan and certain other Asian countries) to relugolix (TAK-385), a phase 3 drug candidate that has been evaluated in over 1,300 patients to date. Relugolix has successfully demonstrated significant clinical benefit and was generally well-tolerated across multiple, large, randomized phase 2 clinical trials in three different indications. Relugolix is being developed as an oral, once-daily, potential best-in-class gonadotropin-releasing hormone (GnRH) receptor antagonist for uterine fibroids, endometriosis and prostate cancer. Takeda will retain commercial rights for relugolix in Asian countries, including Japan, where Takeda is actively conducting two phase 3 registration studies for the treatment of uterine fibroids. Takeda has also granted Myovant an exclusive, worldwide license to RVT-602 (TAK-448), a novel, oligopeptide kisspeptin receptor agonist as a product candidate for the treatment of infertility in females. Financial terms of the partnership were not disclosed.

"With Takeda strengthening its focus around the core therapeutic areas of oncology, gastroenterology and central nervous system diseases, as well as establishing a strategy that embraces innovative partnerships, it is important that we seek alternatives to further develop and create value around promising assets that are either outside these areas of focus or where strategic partnership makes more sense for our business," said Andrew Plump, M.D., Ph.D., Chief Medical and Scientific Officer of Takeda. "The formation of Myovant Sciences represents such an innovative partnership arrangement to further advance relugolix by relying on Roivant’s and Myovant’s in-house development capabilities in the major markets where they are building deep expertise, while leveraging Takeda’s commercial presence in certain Asian territories."

"We are very pleased to partner with Takeda to meet the needs of patients suffering from hormone-driven diseases and disorders," said Vivek Ramaswamy, CEO of Roivant Sciences, Inc. "The creation of Myovant enables a ‘win-win’ outcome for both our partner and for patients by launching a company to address major unmet medical needs in women’s health, prostate cancer and beyond."

Appointment of Dr. Lynn Seely as President & Chief Executive Officer
Lynn Seely, MD, brings over 20 years of drug development and biopharmaceutical company leadership to her role as the President & Chief Executive Officer of Myovant Sciences, Inc. Most recently, Dr. Seely served as Chief Medical Officer of Medivation, Inc. from its early stages in March 2005 through October 2015. She served on the Executive Committee and led the development of XTANDI for the treatment of metastatic castration-resistant prostate cancer from IND-enabling studies through to NDA approval and post-approval clinical studies. Dr. Seely was responsible for building the clinical organization at Medivation, as well as the regulatory, quality, project management, medical affairs and biologics manufacturing functions. Dr. Seely currently serves on the board of directors of Blueprint Medicines Corporation, and she previously served as Vice President of Clinical Development at Anesiva, Inc. (formerly Corgentech) and at Cytyc Health Corporation. Dr. Seely received a medical degree from the University of Oklahoma College of Medicine and completed her residency in internal medicine at Yale-New Haven Hospital. After serving as Chief Resident in Internal Medicine at Yale University School of Medicine, she completed her basic science and clinical fellowship in endocrinology and metabolism at the University of California, San Diego.
"I look forward to delivering on Myovant’s mission to bring innovative new treatments to women suffering from diseases such as uterine fibroids and endometriosis and to men with prostate cancer," stated Dr. Lynn Seely, President & CEO of Myovant Sciences, Inc. "Relugolix and our partnership with Takeda represent an exceptional foundation on which to build this exciting new company."

About Relugolix
Relugolix is a once-daily, orally administered, potential best-in-class gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of uterine fibroids and endometriosis, and a potential best- and first-in-class treatment for hormone-sensitive prostate cancer (HSPC). Relugolix has been evaluated in over 1,300 patients to date, and has successfully demonstrated significant clinical benefit and was generally well-tolerated across multiple, large, randomized phase 2 clinical trials in three different indications. Takeda is currently enrolling two phase 3 clinical trials of relugolix for registration in Japan for the treatment of uterine fibroids.

By inhibiting GnRH receptors in the pituitary gland, relugolix rapidly reduces circulating sex hormone levels leading to suppression of estrogen and testosterone. Suppression of these sex hormones improves the symptoms of women with uterine fibroids and endometriosis, and decreases prostate-specific antigen (PSA) levels in men with HSPC.

In a 216-patient phase 2 study for the treatment of uterine fibroids, women who received relugolix had a significant reduction in menorrhagia, or abnormally heavy bleeding during menstruation. In a 487-patient phase 2 study for the treatment of endometriosis, women who received relugolix had a significant reduction in both non-menstrual and menstrual pelvic pain. Based on these results, two phase 3 registration studies in women with uterine fibroids are underway in Japan (NCT02655237, NCT02655224). In two phase 2 studies in approximately 225 men with HSPC, which included control arms of either an injectable GnRH agonist (leuprolide acetate) or a GnRH antagonist (degarelix), respectively, oral once-daily relugolix suppressed serum testosterone to castrate levels and decreased PSA. The safety of relugolix across all phase 2 studies was generally well-tolerated, consistent with the mechanism of action.

The clinical experience to date, supported by an extensive preclinical development program, suggests that oral relugolix, administered once-daily, could be an important advancement in the treatment options available for women suffering from endometriosis and uterine fibroids. In addition, relugolix could provide men with HSPC an important new treatment option as the first oral GnRH receptor antagonist that offers an alternative to injectable therapies.

About RVT-602
RVT-602 (TAK-448) is a kisspeptin analog that acts to stimulate the physiologic release of GnRH and downstream hormones important in fertility such as luteinizing hormone. Recent evidence from trials performed in women undergoing In-vitro Fertilization (IVF) revealed that the native kisspeptin peptide has the potential to act as an alternative to human chorionic gonadotropin (hCG) or GnRH agonists in triggering egg maturation, an essential step in every IVF cycle.

About Myovant Sciences
Myovant Sciences is focused on innovative treatments for women’s health conditions and prostate cancer. The company’s lead program is relugolix, a phase 3 drug candidate for multiple indications, including uterine fibroids, endometriosis and prostate cancer. Myovant was formed through a strategic partnership between Roivant Sciences and Takeda. Additional information about Myovant Sciences is available through its website, www.myovant.com

On June 6, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPID) ("DelMar" and the "Company"), a company focused on developing and commercializing proven cancer therapies in new orphan drug indications, reported new data from its recently completed Phase I/II clinical trial of VAL-083 (dianhydrogalactitol) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) Annual Meeting on Saturday, June 4, 2016 (Press release, DelMar Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513039]).

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 year’s ASCO (Free ASCO Whitepaper) meeting was an opportunity to share the aggregate of our research to date with the global cancer research community," stated Jeffrey Bacha, chairman and CEO of DelMar Pharmaceuticals. "Based on our findings related to VAL-083’s unique mechanism of action and data from our Phase I/II clinical trial we believe that VAL-083 has the potential to offer a new treatment option for cancer patients whose tumors exhibit features correlated with resistance to currently available chemotherapy."

DelMar’s abstract entitled, "Phase I/II Study of Dianhydrogalactitol in Patients with Recurrent Glioblastoma", was presented during the Central Nervous System poster session on Saturday. The poster presentation can be viewed on DelMar’s website.

In summary, DelMar’s presentation noted:

VAL-083 attacks cancer cells via a unique mechanism of action which is distinct from other chemotherapies used in the treatment of glioblastoma multiforme (GBM). Specifically, VAL-083 is active independent of MGMT, a DNA repair enzyme which is highly expressed in approximately 2/3 of GBM patients and correlated with resistance to temozolomide, the current front-line chemotherapy in the treatment of GBM. Of patients tested in the DelMar trial, 84% exhibited high MGMT.
Median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months, suggesting that VAL-083 may offer improved survival for GBM patients following bevacizumab (Avastin) failure in comparison to currently available salvage therapy. Median survival for VAL-083 treated patients following bevacizumab failure compared with published literature demonstrating survival of approximately three to five months with common salvage therapy regimens.
VAL-083 compared to published literature

Reference
Post Avastin
Salvage Therapy
Median Survival from
Bevacizumab Failure

Rahman (2014)
nitrosourea
4.3 months

Mikkelson (2011)
TMZ + irinotecan
4.5 months

Lu (2011)
dasatinib
2.6 months

Reardon (2011)
etoposide
4.7 months

Reardon (2011)
TMZ
2.9 months

Iwomoto (2009)
various
5.1 months

DelMar Trial
VAL-083
8.35 months

A dose of 40 mg/m2/day VAL-083 administered on the first three days of every three week cycle is well tolerated in refractory GBM patients and has been selected for study in subsequent clinical trials.
DelMar recently announced the completion of a successful end of Phase II meeting with the US FDA and its plans to advance VAL-083 into a pivotal clinical trial for GBM patients whose tumors have recurred following front-line therapy and second line treatment with bevacizumab.

DelMar’s advanced development program will feature a single randomized Phase 3 study measuring survival outcomes compared to a "physicians’ choice" control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in the treatment of Avastin-failed GBM. The final pivotal trial design will be confirmed with the FDA following further discussions with the Company’s clinical advisors.

In addition to the pivotal trial, DelMar also plans to initiate two separate Phase II clinical trials in earlier-stage GBM patients.

A randomized, non-comparative, biomarker-driven, Phase 2 study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 or CCNU improves overall survival at 9 months, compared to historical control in bevacizumab naïve patients. (clinicaltrials.gov identifier: NCT02717962)
A single arm Phase 2 clinical trial to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy (XRT) and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high levels of MGMT.
"We wish to thank the patients, their families, and the physicians who participated in our Phase I/II clinical trial," said Mr. Bacha. "We are pleased to be advancing VAL-083 into these new trials that we believe, if successful, will serve as the basis for a new treatment paradigm in the treatment of GBM."

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 USFDA’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 conducted a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies. Patients were 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) (clinicaltrials.gov identifier: NCT01478178). DelMar announced the completion of enrollment in a Phase II expansion cohort in September, 2015.

About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and most malignant form of brain cancer. Approximately 15,000 people are diagnosed with GBM each year in the U.S., with similar incidence in Europe. Standard of care is surgery, followed by either radiation therapy, or radiation therapy combined with temozolomide. Approximately 60 percent of GBM patients treated with temozolomide experience tumor progression within one year. More than half of glioblastoma patients will fail the currently approved therapies and face a very poor prognosis.

On June 6, 2016 Amgen (NASDAQ:AMGN) reported data from a secondary analysis of the pivotal Phase 3 ASPIRE trial that showed Kyprolis (carfilzomib) for Injection in combination with lenalidomide and dexamethasone (KRd) improved progression-free survival (PFS) and overall response rate (ORR) compared to lenalidomide and dexamethasone (Rd) alone in patients with relapsed multiple myeloma with early disease progression after initial therapy or transplant (Press release, Amgen, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175458 [SID:1234513065]). The results were presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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 analysis showed that patients relapsing within one year of initial therapy treated with KRd (n=87) experienced a median PFS of 24.1 months versus 12.5 months in those treated with Rd (n=72) (HR=0.75; 95 percent CI: 0.50-1.13). In addition, ORR in the KRd arm was 79.3 percent versus 61.1 percent in the Rd arm. Patients relapsing early after first prior transplant treated with KRd (n=48) experienced a median PFS of 17.3 months versus 11.1 months in those treated with Rd (n=49) (HR=0.87; 95 percent CI: 0.54-1.41). In addition, the ORR in the KRd arm was 83.3 percent versus 61.2 percent in the Rd arm. Grade 3 adverse events that occurred at least five percent more frequently in the KRd arm compared to the Rd arm in either subgroup were hypokalemia, neutropenia, febrile neutropenia, hypophosphatemia and respiratory tract infection (ASCO abstract #8045).

"A goal in treating relapsed multiple myeloma is to get patients into remission, and keep them in remission as long as possible. For some patients who relapse early, this may be a sign of a more aggressive disease1," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This analysis showed that in early relapsing multiple myeloma patients, the addition of Kyprolis to lenalidomide and dexamethasone resulted in patients living longer without their disease progressing, a significant milestone for patients living with this difficult-to-treat disease."

ASCO Abstract #8045: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) vs. Lenalidomide and Dexamethasone (Rd) in Patients with Relapsed Multiple Myeloma (RMM) and Early Progression During Prior Therapy: Secondary Analysis From the Phase 3 Study ASPIRE (NCT01080391)

An exploratory sub-group analysis assessed the efficacy and safety of KRd compared with Rd alone in 159 patients with multiple myeloma who had relapsed less than or equal to one year from their first treatment. A second sub-group analysis examined 97 patients with multiple myeloma who had relapsed less than or equal to one year from prior transplant.

In patients who had relapsed less than or equal to one year from their first treatment, median PFS in the KRd arm was 24.1 months versus 12.5 months for Rd (HR=0.75; 95 percent CI: 0.50-1.13), and ORR was 79.3 percent for KRd versus 61.1 percent for Rd. In addition, 21.8 percent of patients in the KRd arm experienced a complete response versus 4.2 percent treated with Rd.
In patients who had relapsed less than or equal to one year after transplant, median PFS in the KRd arm was 17.3 months versus 11.1 months for Rd (HR=0.87; 95 percent CI: 0.54-1.41), and ORR was 83.3 percent for KRd versus 61.2 percent for Rd. Complete responses in the KRd and Rd arms were 12.5 percent and 4.1 percent, respectively.
Grade 3 or higher adverse events that occurred in greater than or equal to five percent more frequently in KRd than Rd in both groups were hypokalemia, neutropenia, febrile neutropenia, hypophosphatemia and respiratory tract infection.
About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated Kyprolis in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.2 It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.2,3 In the U.S., there are nearly 90,000 people living with, or in remission from, multiple myeloma.4 Approximately, 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.5

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

About Kyprolis (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.5 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.5,6

Kyprolis is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

For more information, please visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

INDICATIONS

KYPROLIS (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
KYPROLIS (carfilzomib) is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients > 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuroradiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse events occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse events occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full Prescribing Information at www.kyprolis.com.

On June 6, 2016 Threshold Pharmaceuticals, Inc. (NASDAQ:THLD) reported multiple presentations on clinical trials on its hypoxia-activated prodrugs, evofosfamide and tarloxotinib at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 3 through 7, 2016 in Chicago, Ill (Press release, Threshold Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513086]).

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!

Today, Threshold presented additional data from its analysis of the randomized, double-blind Phase 3 MAESTRO clinical trial of evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma conducted by Merck KGaA. A meaningful improvement in overall survival was reported for the subgroup of 123 Asian patients enrolled at Japanese and South Korean sites in which the risk of death was reduced by 48 percent for patients on the treatment arm compared to patients on the control arm with an associated stratified hazard ratio of 0.52 (95% CI: 0.32 – 0.85). The patients from Asia also had significant improvements in PFS, objective response rates, and reductions in the pancreatic cancer biomarker, CA19-9 (abstract 4007). As previously reported in January 2016, the primary efficacy endpoint of this study of overall survival narrowly missed statistical significance based on specified intent-to-treat analysis while showing improvements in secondary efficacy endpoints of progression-free survival (PFS) and response.

On June 4, 2016, the following posters were displayed:

Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide and Pemetrexed in Second Line Advanced Non-Squamous Non-Small Cell Lung Cancer. Csoszi et al. (abstract 9075).

As reported in January 2016, the study was stopped early based on a futility analysis of overall survival conducted by the study Data and Safety Monitoring Board (DSMB). The study enrolled 265 patients of a planned 440 patients. The response rate with evofosfamide plus pemetrexed was 18.0 percent and significantly higher compared to 8.1 percent with placebo plus pemetrexed. The median PFS with evofosfamide plus pemetrexed was 4.5 months (95% CI: 4.0 to 6.4 months) and significantly higher compared to 2.9 (95% CI: 2.6 to 4.1) months with placebo plus pemetrexed. Hematologic toxicity was greater in the evofosfamide plus pemetrexed arm, while non-hematologic toxicity was similar across treatment arms. No new safety signals were identified.

Evofosfamide combined with gemcitabine/nab-paclitaxel in patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma (PAC): results of a phase I trial. Borad et al. (abstract 4114).

Nineteen patients were treated for a median of 6 cycles. The maximum tolerated dose of evofosfamide was established at 340 mg/m2 in combination with 800 mg/m2 gemcitabine and 100 mg/m2 nab-paclitaxel. No new safety signals were identified with myelosuppression being the primary dose limiting toxicity. The best response rate was 53 percent and the confirmed response rate was 37 percent.

Two additional trials-in-progress posters were also displayed:

A Phase 2 Study of Tarloxotinib Bromide (TRLX) in Patients with Recurrant or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) or Skin (SCCS).
Rischin et al. (abstract TPS6105)

A Phase 2 Study (NCT02454842) of Tarloxotinib Bromide (TH-4000) in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI.
Liu et al. (abstract TPS9100)

Copies of the posters may be obtained from Threshold’s website, www.thresholdpharm.com, under Scientific Publications.

About Evofosfamide
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug of a bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic. On December 6, 2015, the Company announced the outcomes of two Phase 3 studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide stating that neither study met its primary endpoint.

About Tarloxotinib Bromide
Tarloxotinib bromide (the proposed International Nonproprietary Name, previously known as TH-4000), or "tarloxotinib", is a prodrug designed to selectively release a covalent (irreversible) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the systemic side effects associated with currently available EGFR tyrosine kinase inhibitors. Tarloxotinib is currently being evaluated in two Phase 2 proof-of-concept trials: one for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR tyrosine kinase inhibitor, and the other for patients with recurrent or metastatic squamous cell carcinomas of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

On June 6, 2016 Array BioPharma (Nasdaq: ARRY) reported full results at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Abstract No. 9500) from the pivotal Phase 3 NEMO (NRAS MELANOMA AND MEK INHBITOR) trial of binimetinib (Press release, Array BioPharma, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175437 [SID:1234513066]). The study found binimetinib significantly extended median progression-free survival (PFS), the study’s primary endpoint, at 2.8 months, as compared with 1.5 months observed with dacarbazine [hazard ratio (HR)=0.62 (95% CI 0.47-0.80), p<0.001] – the first trial to ever meet a PFS endpoint in patients with advanced NRAS-mutant melanoma. In the pre-specified subset of patients who received prior treatment with immunotherapy, including ipilimumab, nivolumab or pembrolizumab, patients who received binimetinib experienced 5.5 months of median PFS (95% CI, 2.8–7.6), compared with 1.6 months for those receiving treatment with dacarbazine (95% CI, 1.5–2.8).

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!

Array BioPharma. (PRNewsFoto/Array BioPharma Inc.)
"The NEMO findings are promising and suggest binimetinib may provide a new treatment option for the thousands of patients who are diagnosed with NRAS-mutant melanoma," said lead study investigator Reinhard Dummer, M.D., Professor, Dept. of Dermatology, University of Zurich Hospital. "Particularly compelling are the results in the pre-specified sub-group of patients who had received prior treatment with immunotherapy, which is now recognized as the standard of care for first-line treatment in this patient population."

In addition to improving PFS, binimetinib also demonstrated significant improvement in overall response rate (ORR) and disease control rate (DCR). While there was no statistically significant difference demonstrated in overall survival, the median overall survival (mOS) favored the binimetinib arm.

Confirmed ORR was 15 percent (95% CI, 11-20 percent) in patients receiving binimetinib vs. 7 percent (95% CI, 3-13 percent) in patients receiving dacarbazine.
DCR for patients receiving binimetinib was 58 percent (95% CI, 52-64 percent) vs. 25 percent (95% CI, 18-33 percent) for patients receiving dacarbazine.
mOS was estimated at 11.0 months in patients receiving binimetinib vs. 10.1 months for patients treated with dacarbazine [(HR) = 1.0 (95% CI 0.75-1.33), p=0.499].
"NRAS-mutant melanoma impacts one out of five advanced melanoma patients, yet there are currently no treatment options indicated specifically for these patients," said study investigator Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School. "There remains a need for additional effective treatments for patients with NRAS–mutant disease. Binimetinib may provide another important treatment option for this patient population."

Binimetinib was generally well-tolerated and the adverse events (AEs) reported were consistent with previous results in NRAS-mutant melanoma patients. Grade 3/4 AEs reported in greater than or equal to 5 percent of patients receiving binimetinib included increased creatine phosphokinase (CPK) and hypertension.

"The NEMO trial results demonstrate the potential of binimetinib to help slow disease progression in this patient population, an often overlooked subset without treatment options beyond immunotherapy," explained Victor Sandor, M.D., Chief Medical Officer, Array BioPharma. "Based on the strength of these data, we plan to submit our regulatory filing for binimetinib in NRAS-mutant melanoma later this month."

About NEMO
The NEMO trial, (NCT01763164), is an international, randomized Phase 3 study in patients with advanced NRAS-mutant melanoma. 402 patients were randomized 2:1 to receive continuous 45 mg BID binimetinib or 1,000 mg/m2 dacarbazine dosed every three weeks. Prior immunotherapy treatment was allowed. The primary endpoint of the study is progression-free survival, and overall survival is a key secondary endpoint. Patients underwent radiographic assessment of disease status every six weeks, and assessment of progression was determined by blinded central review. Over 100 sites across North America, Europe, South America, Asia and Australia participated in the study.

About NRAS-Mutant Melanoma
Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and nearly 10,000 deaths from the disease projected in 2016. Activating NRAS mutations are present in up to 20 percent of patients with metastatic melanoma, and is a poor prognostic indicator for these patients. Treatment options for this population remain limited beyond immunotherapy, and patients face poor clinical outcomes and high mortality.

About Binimetinib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, non-small cell lung, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor, which targets key enzymes in this pathway.

Binimetinib is currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer. Array projects COLUMBUS top-line results availability during the third quarter of 2016.