On January 13, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas US LLC, a subsidiary of Tokyo-based Astellas Pharma Inc. (TSE: 4503), reported that results from the Phase 2 TERRAIN trial of enzalutamide compared to bicalutamide in metastatic castration-resistant prostate cancer (CRPC) were published in the Lancet Oncology (Press release, Medivation, JAN 13, 2016, View Source [SID:1234508790]). The article, titled, "Efficacy and Safety of enzalutamide Versus bicalutamide for Patients with Metastatic Prostate Cancer (TERRAIN)," appears in the January 13th online issue and will be published in a future print issue of the journal.

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 TERRAIN study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval, 0.34-0.57; p < 0.0001). Median PFS, defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy or death, whichever occurred first, was 15.7 months in the enzalutamide group compared to 5.8 months in the bicalutamide group. The observed adverse event profile of enzalutamide in TERRAIN appeared consistent with that from Phase 3 enzalutamide trials.

"TERRAIN is the first and largest head-to-head trial comparing enzalutamide with bicalutamide that evaluated both the efficacy and safety of these agents in the treatment of men with mCRPC," said Claire Thom, Pharm D., senior vice president and oncology therapeutic head, Astellas. "We are pleased Lancet Oncology has chosen to publish these results."

The median time on treatment in TERRAIN was 11.7 months in the enzalutamide group versus 5.8 months in the bicalutamide group. Serious adverse events were reported in 31.1% of enzalutamide-treated patients and 23.3% of bicalutamide-treated patients. Individual Grade 3 or higher adverse events largely occurred at a similar rate ( < 1% difference) between treatment groups, with the exception of hypertension (7.1% vs. 4.2%) and back pain (2.7% vs. 1.6%), which occurred more frequently in the enzalutamide treatment group. Grade 3 or higher cardiac events were reported in 5.5% of enzalutamide-treated patients versus 2.1% of bicalutamide-treated patients. Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common side effects occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, back pain, hot flush, hypertension, diarrhea, weight decreased and pain in extremity.

About the TERRAIN trial
The Phase 2 TERRAIN trial enrolled 375 patients in North America and Europe. The trial enrolled patients with metastatic prostate cancer whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy or following surgical castration. The primary endpoint of the trial was PFS, defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy or death, whichever occurred first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with an LHRH analogue.

About XTANDI (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that acts on multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA.

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re- administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.

Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit www.XtandiHCP.com

On January 13, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that its European subsidiary has entered into a research and license agreement with Leiden University Medical Center (LUMC) to identify and develop T cell receptor (TCR) product candidates targeting solid tumors that are associated with the human papillomavirus (HPV) type 16 infection (Press release, Kite Pharma, JAN 13, 2016, View Source [SID:1234508789]).

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!

Under the terms of the agreement, Kite Pharma EU will partner with the LUMC Department of Clinical Oncology and Professor Dr. Sjoerd van der Burg, a leader in the research of HPV-associated cancers. Kite will also receive an exclusive option to license multiple TCR gene sequences for the development and commercialization of product candidates.

"This collaboration expands our existing TCR franchise targeting HPV-associated cancers and creates an opportunity to broaden the coverage of human leukocyte antigen (HLA) types across different patient populations," said David Chang, M.D., Ph.D., Chief Medical Officer and Executive Vice President of Research and Development of Kite. "LUMC is an ideal partner, given its deep experience with the immune response to solid tumors, and complements our existing research and development capabilities in Europe."

Kite Pharma EU, based in Amsterdam, is focused on the discovery and development of tumor-specific TCRs for broad use in cancer treatment based on its TCR-GENErator platform. Kite Pharma EU is comprised of a leading team of immuno-oncology researchers and collaborators, including Professor Dr. Ton N. M. Schumacher, who serves as Chief Scientific Officer.

About HPV-Associated Cancers

There were over 525,000 new cases of and 265,000 deaths attributable to cervical cancer worldwide in 2012.1 HPV is the most common viral infection of the reproductive tract, and HPV-16 is believed to cause about 50-60% of cervical cancers. HPV-16 is also implicated in additional anogenital and head and neck cancer types,2 and is believed to cause 90% of HPV-mediated oropharyngeal cancers and the majority of HPV-mediated anal, penile, vaginal and vulvar cancers.

About Leiden University Medical Center

LUMC is a modern university medical center for research, education and patient care with a high quality profile and a strong scientific orientation. The Department of Clinical Oncology performs scientific research on the immune response to solid tumors, and in particular focuses on ways by which immunomodulation can help improve the outcome of treatment of patients with solid tumors, including human papillomavirus-driven cancers, ovarian cancer and melanoma. Current strategies aim at improving the immune response against cancer cells by therapeutic vaccination, targeting new checkpoint molecules, administration of ex vivo expanded T-cells, and/or oncolytic viruses, in combination with chemotherapy and other immune modulators.

On January 13, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX) reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for FPA008 for the treatment of Pigmented Villonodular Synovitis (PVNS), a locally aggressive tumor of the synovium (Press release, Five Prime Therapeutics, JAN 13, 2016, View Source [SID:1234508786]).

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!

"PVNS is a painful joint disease for which there are no currently approved treatments," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "FPA008 is our investigational antibody that we believe blocks the activation and survival of the macrophages that make up the bulk of the PVNS tumor. This orphan drug designation by the FDA highlights the need for new treatments to help patients with this rare disease."

Orphan Drug Designation is granted by the FDA Office of Orphan Drug Products to products that treat rare diseases. The FDA defines rare diseases as those affecting fewer than 200,000 people in the United States. Orphan Drug Designation provides the sponsor certain benefits and incentives, including a period of marketing exclusivity for the first marketing application, if regulatory approval is received for the designated indication, potential tax credits for certain activities and waiver of certain administrative fees.

About PVNS
PVNS is a rare, locally aggressive tumor of the synovium. It is characterized by local over-expression of CSF-1, which recruits macrophages into the joints, forming the non-malignant tumor mass. It is associated with high morbidity, and there are no approved therapies for the condition. FPA008 blocks the binding of CSF-1 and inhibits the activity and survival of the macrophages that form the bulk of the tumor. Five Prime is currently in a Phase 1 clinical trial studying FPA008 as a treatment for PVNS.

About FPA008
FPA008 is an investigational antibody that inhibits CSF1R and has been shown in preclinical models to block the activation and survival of monocytes and macrophages. Inhibition of CSF1R in preclinical models of several cancers reduces the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment, thereby facilitating an immune response against tumors. FPA008 is currently in phase 1 clinical trials in PVNS and oncology indications. FPA008 is being developed under an exclusive worldwide license and collaboration agreement with Bristol-Myers Squibb (BMS).

On January 13, 2016 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number:4875), reported receipt from the European Patent Office of a notice of intent to allow patent for MN-029 (denibulin) di-hydrochloride (Press release, MediciNova, JAN 13, 2016, View Source [SID:1234508785]).

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!

Once issued, the patent maturing from this allowed patent application is expected to expire no earlier than July 2032. The allowed claims cover the compound, pharmaceutical compositions and a method of treating certain cell proliferative diseases, including cancer, using MN-029 (denibulin) di-hydrochloride. MediciNova intends to use MN-029 (denibulin) di-hydrochloride in future development.

"We are very pleased that the European Patent Office will grant our compound patent for MN-029 as we believe it could substantially increase the potential value of MN-029. We will now consider developing a program for MN-029 in Europe," commented Yuichi Iwaki, MD, PhD, President and CEO of MediciNova, Inc.

About MN-029

MN-029 is a novel, small molecule vascular disrupting agent (VDA) being developed for the treatment of solid tumor cancers. MediciNova licensed MN-029 from Angiogene Pharmaceuticals, Ltd. Several preclinical pharmacology studies conducted by Angiogene Pharmaceuticals and MediciNova have assessed the mechanism of action and anti-tumor activity of MN-029 in vivo in rodent models of breast, adrenocarcinoma, colon carcinoma, lung carcinoma and KHT sarcoma. In these studies, MN-029 damaged poorly formed tumor blood vessels by weakening tumor blood vessel walls and causing leakage, clotting and eventual vascular shutdown within the tumor. These studies suggest that MN-029 acts quickly and is rapidly cleared from the body, which may reduce the potential for some adverse effects commonly associated with chemotherapy. Shutdown of tumor blood flow in tumor models was confirmed through the use of dynamic contrast-enhanced MRI. In two Phase 1 clinical studies conducted by MediciNova, MN-029 was well-tolerated at doses that reduced tumor blood flow.

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!
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!

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.

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.