On June 2, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma Inc. (TSE: 4503) reported plans to commence a Phase III clinical trial to investigate the use of enzalutamide for the treatment of triple-negative breast cancer (TNBC) (Press release, Medivation, JUN 2, 2016, View Source [SID:1234512954]).

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 ENDEAR (A Phase III, Randomized, International Study Comparing the Efficacy and Safety of ENzalutamiDe in Combination With PaclitaxEl Chemotherapy or as Monotherapy Versus Placebo With Paclitaxel in Patients With Advanced, Diagnostic-Positive, Triple-Negative BReast Cancer) trial will evaluate the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC whose tumors test positive for a novel gene expression profile, which is referred to as diagnostic-positive TNBC. The trial, which will be led by Medivation, is expected to begin patient enrollment in the fourth quarter of 2016.

In the United States, breast cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer deaths in women. According to the American Cancer Society, approximately 246,000 new cases of breast cancer will be diagnosed in women and 40,000 women will die of breast cancer in 2016.1 Approximately 15-20 percent of breast cancers are triple negative or basal-like, the subtype that the ENDEAR trial will study.2 Patients with TNBC have a poor prognosis3 and there are currently no therapies specifically approved to treat this patient population.

"Our initiation of this trial represents our commitment to explore the potential of enzalutamide in patients with advanced TNBC," said Mohammad Hirmand, M.D., interim chief medical officer, Medivation.

"The initiation of the ENDEAR trial reflects our ongoing commitment to investigate the full clinical utility of enzalutamide," said Claire Thom, Pharm D., senior vice president and oncology therapeutic area head, Astellas.

Enzalutamide, which is known by the brand name XTANDI, is not approved for use in patients with TNBC.

About ENDEAR
ENDEAR will be a Phase III, randomized, international trial, enrolling approximately 780 patients with advanced diagnostic-positive TNBC who have received either no or one prior line of systemic therapy for advanced disease. The primary efficacy endpoint is progression-free survival (PFS), defined as the time from randomization to the first evidence of disease progression or death, whichever occurs first. The trial will evaluate enzalutamide at a dose of 160 mg per day taken orally, either with paclitaxel (90 mg/m2) administered intravenously once weekly for 16 weeks (or longer at investigator discretion), or as monotherapy compared to placebo with paclitaxel.

About XTANDI (enzalutamide) capsules
XTANDI (enzalutamide) capsules are 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 as well as 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 (mCRPC).

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.

On June 2, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported it has entered into a research agreement with Leiden University Medical Center (LUMC), Netherlands, to discover and validate natural high-affinity TCR (T cell receptor) product candidates targeting several cancers (Press release, Bellicum Pharmaceuticals, JUN 2, 2016, View Source [SID:1234512952]). The new collaboration builds on an earlier agreement with LUMC that gave Bellicum worldwide rights to TCR product candidates targeting solid tumors that express PRAME (preferentially-expressed antigen in melanoma) and other antigens.

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!

"We are enthusiastic about the potential of TCRs that incorporate our switch technology to produce a targeted, potent and controlled attack on certain cancers," said Tom Farrell, President and Chief Executive Officer of Bellicum Pharmaceuticals. "Dr. Mirjam Heemskerk and her group from the Department of Hematology of the LUMC, have made significant breakthroughs in the development of natural high-affinity TCRs, and we look forward to their continued discoveries as we prepare to launch clinical studies this year of our first TCR, BPX-701, under our current license from Leiden."

Under terms of the new collaboration, Bellicum will provide financial support to LUMC over a three-year term in exchange for the right to exclusively license any high-affinity TCRs discovered under the agreement.

TCRs are engineered T cells that become activated in the presence of cancer cells containing a target antigen. Bellicum’s first TCR product candidate, BPX-701 targeting PRAME, is expected to enter Phase 1/2 clinical trials in mid-2016 to treat refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). BPX-701 was licensed from Leiden in 2015 and incorporates Bellicum’s proprietary safety mechanism, CaspaCIDe, for improved control over the cells.

On June 1, 2016 Oncternal Therapeutics, Inc. and Tokalas, Inc., reported that the two companies have completed a merger to create a new world-class clinical-stage oncology company with two promising, first-in-class pipeline products (Press release, Oncternal Therapeutics, JUN 2, 2016, View Source [SID:1234512921]). The transaction was approved by both companies’ shareholders, and results in the combination of all assets, research and developments programs and operations under the name Oncternal Therapeutics, 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!

"We are merging two San Diego companies developing clinical-stage therapeutic candidates against novel and important cancer targets, creating an exciting new oncology company with a clinical-stage pipeline spanning multiple technologies and cancer indications," said Dr. James Breitmeyer, President and CEO. "Common regulatory and development strategies result in significant synergies for the combined company. Our highly experienced management team will lead Oncternal forward and rapidly advance our two products, cirmtuzumab and TK216, into additional clinical trials for some of the most devastating and underserved forms of cancer."

The Oncternal board of directors and management team has extensive experience in the formation and successful development of biotechnology companies and innovative pharmaceutical products. The company announced key leadership appointments including:

President and CEO will be James B. Breitmeyer, M.D. and Ph.D., an oncologist with over 25 years in the industry who has led efforts resulting in approval of eight US or international product approvals.
The board of directors will be chaired by Dave Johnson, who most recently led Acerta to a strategic transaction with AstraZeneca valued at up to $7 billion. The other initial board members will be David Hale, Cam Garner, Scott Glenn, and James Breitmeyer, who have been involved in founding and/or developing over thirty successful life sciences companies.

As a combined company, Oncternal Therapeutics will hold exclusive worldwide development and commercialization rights to two clinical-stage oncology products with potential across a range of cancer indications:

Cirmtuzumab, a first-in-class anti-ROR1 monoclonal antibody, currently in a phase 1 clinical trial for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Cirmtuzumab was developed by Thomas Kipps, M.D. at the Moores Cancer Center of UC San Diego, who conducted extensive research to characterize the function and expression of ROR1, which may identify cancer stem cells in a number of hematologic malignancies and solid tumors. Oncternal and UC San Diego are planning studies in CLL, breast cancer and mantle cell lymphoma this year. Oncternal also has rights to develop antibody-drug conjugates (ADCs), genetically modified effector immune cells, such as chimeric antigen receptor T-cells (CAR-T), and bispecific antibodies related to ROR1.

TK216, a first-in-class small molecule ets-family transcription factor inhibitor, about to enter phase 1 testing for patients with Ewing sarcoma. TK216 is based upon the discoveries of Jeffrey A. Toretsky, M.D. at Georgetown University, who conducted extensive research on the ets-family oncogenic translocations that cause or drive tumor growth in a number of solid and hematologic malignancies. Oncternal and Georgetown are planning clinical studies in Ewing sarcoma, glioblastoma and prostate cancer in the next year.