On March 24, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma Inc. (TSE: 4503) reported that the ARCHES (AR Inhibition with ChemoHormonal Therapy in Men with MEtastatic Castrate Sensitive Prostate Cancer) Phase III registrational trial, which will evaluate the efficacy and safety of enzalutamide with androgen deprivation therapy (ADT) versus placebo with ADT in metastatic hormone sensitive prostate cancer (mHSPC) patients, has been initiated and the first patient has been randomized (Press release, Medivation, MAR 24, 2016, View Source [SID:1234509925]).

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Prostate cancer is the most commonly diagnosed cancer and the second-leading cause of cancer death in men in the United States. According to the American Cancer Society, approximately 181,000 new cases of prostate cancer will be diagnosed, and 26,000 men will die of prostate cancer in the United States in 2016.i Androgen deprivation therapy, which reduces the levels of androgens (male hormones), is the standard of care for patients with mHSPC. The ARCHES trial will investigate whether the addition of enzalutamide to ADT may benefit this patient population compared to ADT alone.

"This trial targets an important patient population as we advance the development of enzalutamide," said Mohammad Hirmand, M.D., interim chief medical officer, Medivation. "The initiation of this trial demonstrates our ongoing commitment to fully develop enzalutamide in this serious disease."

"Dosing of the first patient in this trial demonstrates our ongoing commitment to continuing to investigate enzalutamide," said Claire Thom, Pharm D., senior vice president and oncology therapeutic area head, Astellas.

The global, Phase III, randomized, double-blind, placebo-controlled study, which is being led by Astellas, will evaluate the efficacy and safety of enzalutamide with ADT versus placebo with ADT in patients with mHSPC. ARCHES will enroll approximately 1,100 patients with mHSPC at approximately 250 centers globally. The primary endpoint of the trial is radiographic progression-free survival (rPFS), defined as the time from randomization to the first objective evidence of radiographic disease progression as assessed by central review or death, whichever occurs first. The trial will evaluate enzalutamide at a dose of 160 mg to be taken orally once daily versus placebo, administered with ADT.

For more information about this trial, visit www.clinicaltrials.gov, trial identifier NCT02677896.

Enzalutamide is being developed through a collaboration between Medivation and Astellas. Enzalutamide, which is known by the brand name XTANDI, is not approved for use in patients with metastatic hormone sensitive prostate cancer (mHSPC).

About XTANDI
XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks 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. The clinical significance of this MOA is unknown.
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

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 View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1‐800‐FDA‐1088.

On March 24, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that the first patient has been dosed in SEASCAPE, the Phase 1/2 clinical study designed to evaluate the safety, tolerability and preliminary efficacy of CRS-207, Aduro’s lead listeria-based immunotherapy construct (LADD), in combination with epacadostat (INCB24360), Incyte Corporation’s (Nasdaq:INCY) selective IDO1 inhibitor, in patients with ovarian cancer (Press release, Aduro BioTech, MAR 24, 2016, View Source [SID:1234509924]).

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"By combining two immuno-oncology therapies which we believe have synergistic mechanisms of action, we and Incyte look forward to potentially advancing new treatment options for patients with ovarian cancer that could result in more effective therapy than either therapy alone," said Stephen T. Isaacs, chairman, president and chief executive officer of Aduro. "Combination therapy is rapidly emerging as a new paradigm for immuno-oncology. With our three diverse technology platforms – LADD (listeria-based therapy), STING pathway activators and monoclonal antibodies – we intend to continue to identify new opportunities to improve patient care."

SEASCAPE (Study of Epacadostat and CRS-207 in Adults with Platinum Resistant Ovarian Cancer), co-funded by Incyte and Aduro, is designed to establish a recommended dose based on safety and tumor biomarkers for CRS-207 and epacadostat in Phase 1 followed by expansion into Phase 2 which will evaluate the combination at the recommended (or identified) dose level compared to CRS-207 alone. Aduro plans to enroll up to 40 patients in Phase 1 and up to 86 patients in Phase 2 with platinum-resistant ovarian, fallopian or peritoneal cancers. For more information about the study, visit www.clinicaltrials.gov and search identifier NCT02575807.

Aduro and Incyte will collaborate on a non-exclusive basis. Aduro will be responsible for conducting the study and the results will be used to determine whether further clinical development of this combination is warranted. Costs for the trial will be shared on an equal basis.

About Epacadostat

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Epacadostat is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity.

Epacadostat has shown proof-of-concept clinical data in patients with unresectable or metastatic melanoma in combination with the CTLA-4 inhibitor ipilimumab, and is currently in four proof-of-concept clinical trials with PD-1 and PD-L1 immune checkpoint inhibitors in a variety of cancer histologies. A Phase 3 study evaluating the combination of epacadostat with pembrolizumab as first-line treatment for patients with advanced or metastatic melanoma is expected to begin in the first half of 2016.

About CRS-207

CRS-207 is one of a family of product candidates based on Aduro’s live, attenuated, double-deleted (LADD) Listeria monocytogenes immunotherapy platform that induces a potent innate and T cell-mediated adaptive immune response. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

On March 24, 2016 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported that the first patients have been treated in the investigator-sponsored VITAL (Vosaroxin and Infusional Cytarabine for Frontline Treatment of Acute Myeloid Leukemia) Phase 2 study of vosaroxin in combination with cytarabine in patients with previously untreated acute myeloid leukemia (AML) (Press release, Sunesis, MAR 24, 2016, View Source [SID:1234509918]).

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The trial is being conducted at the Vanderbilt-Ingram Cancer Center at Vanderbilt University under the direction of Michael R. Savona, M.D., FACP, Associate Professor of Medicine and Director of Hematology Early Therapeutics Program, and Stephen A. Strickland, M.D., MSCI, Assistant Professor of Medicine.

"With an alarming rate of mortality in AML and no major change in induction therapy strategy for nearly four decades, there is an urgent need to find novel therapeutic strategies for this disease," said Dr. Strickland. "Given the established, acceptable safety profile of infusional cytarabine given concomitantly with vosaroxin, this combination offers a new approach for achieving remission in this population. It also provides the opportunity to expand upon the previously observed efficacy of vosaroxin in patients with relapsed/refractory AML and has the potential to serve as a foundation for a future randomized Phase 3 trial."

VITAL, a single-arm, open-label Phase 2 trial will enroll up to 61 previously untreated, newly diagnosed adult patients with AML. During stage 1 of the trial, 17 patients will be enrolled. The study design permits one interim look to examine evidence of futility after the first 17 patients are evaluable for response. If ≤ 7 patients achieve complete remission (CR), the VITAL DSMB will review the clinical data to determine the merits of continued enrollment. If > 7 CRs are observed, the second stage will open automatically and increase enrollment to 41 patients. During both stages, Vosaroxin will be administered intravenously at 90 mg/m2 on days 1 and 4. Cytarabine will be administered in standard fashion as a continuous infusion of 100 mg/m2 daily on days 1-7.

Patients with evidence of residual leukemia on "Day 14 biopsy" following initial induction will be offered re-induction with intravenous vosaroxin at 70 mg/m2 on days 1 and 4 in combination with continuous infusion cytarabine at 100 mg/m2 daily on days 1-7. The primary endpoint of the study is rate of CR. The secondary endpoints are to determine the safety and tolerability, presence of minimal residual disease, CR (including CR with incomplete blood count recovery), neutrophil and platelet recovery, disease free survival (DFS), overall survival (OS), and the correlation of HSCT comorbidity index and Wheatley index scores with disease response, DFS and OS.

"VITAL is the third investigator-sponsored combination trial of vosaroxin in frontline AML, and an important component of establishing our future development strategy in this setting," said Daniel Swisher, Chief Executive Officer of Sunesis. "We look forward to seeing results from these studies, which include two other leading institutions, MD Anderson and Indiana University, as we make progress on the review of our European Marketing Authorization Application for vosaroxin as a treatment for relapsed/refractory AML."

About QINPREZO (vosaroxin)

QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.

The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

On March 24, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported that the National Comprehensive Cancer Network (NCCN) has included ONIVYDE (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin in its 2016 Clinical Practice Guidelines in Oncology for pancreatic adenocarcinoma (Press release, Merrimack, MAR 24, 2016, View Source [SID:1234509915]).

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The new guidelines recognize the ONIVYDE regimen as a category 1 second-line therapy for patients with metastatic adenocarcinoma of the pancreas who have previously been treated with gemcitabine-based therapy. A category 1 classification represents the highest level of evidence and uniform NCCN consensus that the intervention is appropriate. The new guidelines are published on www.nccn.org .

"The addition of the ONIVYDE regimen to the 2016 NCCN guidelines further validates the importance of this treatment option for patients battling metastatic pancreatic cancer," said Edward J. Stewart, Head of Commercial at Merrimack. "ONIVYDE is the only FDA approved therapy available to patients whose disease has progressed after gemcitabine-based therapy and, more importantly, it addresses a critical unmet need in a patient population with very limited options. We believe these guidelines will further support the adoption of the ONIVYDE regimen as a standard-of-care in metastatic pancreatic cancer."

Pancreatic cancer is a rare and deadly disease. Each year approximately 53,000 patients are diagnosed with pancreatic cancer in the United States with only 7% surviving five years or longer1. The NCCN’s recommendation was based on a review by a multidisciplinary panel of experts from NCCN member institutions and supported by data from the NAPOLI-1 study, published in The Lancet in 2015, and the U.S. Food and Drug Administration (FDA) approval of the ONIVYDE regimen. NAPOLI-1 was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in North America, South America, Europe, Asia and Oceania.

NCCN is an alliance of 26 world-class cancer centers dedicated to the development of treatment guidelines for most cancers and to research that will ultimately improve the quality of patient care and outcomes. The NCCN guidelines are widely recognized as the standard of clinical practice in oncology and provide evidence-based treatment recommendations to assist key stakeholders, including physicians, patients and payers, in directing cancer patient care.

About ONIVYDE [pronounced \ ‘on – īh – vide \]

ONIVYDE (irinotecan liposome injection), also known as MM-398 or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. ONIVYDE was recently approved by the U.S. Food and Drug Administration in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. For full prescribing information, including Boxed WARNING, please visit www.ONIVYDE.com.