On April 3, 2015 Astellas Pharma and The University of Texas MD Anderson Cancer Center reported the signing of an option agreement to research and develop a new treatment for patients with acute myeloid leukemia (AML) (Press release, Astellas, APR 3, 2015, View Source [SID:1234502918]).

The collaboration grants Astellas an option to firstly negotiate an exclusive, worldwide license at the end of Phase Ib, with both Phase Ia and Phase Ib studies to be conducted by MD Anderson. The agreement also includes up to $26 million as an option premium and research and development funding.

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The collaboration will focus on h8F4 technology, a humanized monoclonal antibody invented by Jeffrey Molldrem, M.D., professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson. The antibody h8F4 targets an HLA-restricted peptide called PR1/HLA-A2, which is expressed in cancer cells and cancer stem cells. Molldrem will lead these research efforts with Carlo Toniatti, M.D., Ph.D., executive director of MD Anderson’s Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform.

"Current treatments for aggressive leukemias are often toxic," said Molldrem. "We desired to develop a safer, yet more potent, therapy for these aggressive cancer types that currently have poor survival outcomes. Unfortunately, advancing novel discoveries from the laboratory to drug development has been historically challenging. We hope that this important collaboration will allow us to deliver much-needed antibody-based treatment to the patient’s bedside more quickly."

"h8F4 has a radically novel anti-tumor activity and this collaboration provides MD Anderson and Astellas with a great opportunity to potentially deliver a first-in-class antibody drug to patients with AML," commented Yoshihiko Hatanaka, president and CEO of Astellas. "Astellas continues to focus on developing novel therapies in areas of unmet medical need through in-house developments and external collaborations."

While monoclonal antibodies are very common in oncology, generating antibodies against HLA-restricted peptides has proven difficult. To develop viable antibody drugs, MD Anderson created ORBIT for its Moon Shots Program to centralize this type of research. The program is an ambitious initiative to accelerate the conversion of scientific discoveries into clinical advances and significantly reduce cancer deaths.

"This is an outstanding addition to MD Anderson’s Moon Shots Program to deliver accelerated solutions for cancer treatment," said Ronald DePinho, M.D., president of MD Anderson. "These are exciting times for cancer drug development and I’m proud that eminent scientists like Drs. Molldrem and Toniatti are leading the way. While it’s true that myeloid cancer has not responded well to standard therapies, this novel solution looks promising."

On April 2, 2015 BIND Therapeutics reported an extension of the terms of its global collaboration with Pfizer to create Accurins that optimize the therapeutic potential of two molecularly targeted oncology drugs in Pfizer’s pipeline (Press release, BIND Therapeutics, APR 2, 2015, View Source [SID:1234502916]). The collaboration was originally established in April 2013 and the timeline for Pfizer to exercise its option to acquire the exclusive license for the first program continues to be September 2015. Both companies agreed to an extension of the timeline for the second program through March 2016.

“We have made a great deal of progress in this collaboration and have shown promising preclinical results with Accurins containing each of the two compounds,” said Andrew Hirsch, president and chief executive officer, BIND Therapeutics. “Pfizer has been a terrific partner and the results to date have provided evidence that we are on track with the collaboration goals. We mutually agreed to extend the research terms for the second of the two selected compounds in order to ensure it is fully evaluated and well-positioned to enter IND-enabling studies.”

A development milestone was achieved for the first program in December 2014. The 2015 option target date on the first compound remains unchanged and this extension allows BIND and Pfizer an additional year to complete preclinical research evaluating the second program.

“Our Accurin development programs are active and of high interest to both companies,” said Robert Abraham, Ph.D., Senior Vice President and Chief Scientific Officer, Oncology Research Unit, Pfizer. “We are pleased to continue working with BIND under terms of the amended agreement.”

Under terms of the original agreement, Pfizer has the exclusive option to pursue development and commercialization of the Accurins selected. Both companies will work together on preclinical research, and if Pfizer exercises its option, Pfizer will have responsibility for development and commercialization of the selected Accurins.

BIND received an upfront payment of $4.0 million in 2013, a $1.0 million preclinical development milestone in December 2014, and has the potential to receive payments up to $88.5 million upon the achievement of additional specified development and regulatory events. BIND may also receive additional payments up to $110 million for specified commercial events as well as royalties in the low single to high single digit percentages on potential future sales of each Accurin commercialized, if any.

On April 2, 2015 OncoMed Pharmaceuticals reported that it has entered into an agreement with Eli Lilly (Press release, OncoMed, APR 2, 2015, View Source [SID:1234502914]). Demcizumab, OncoMed’s anti-DLL4 antibody, is being tested in combination with Lilly’s Alimta (pemetrexed for injection) and carboplatin for the treatment of first-line advanced non-small cell lung cancer (NSCLC). Under the terms of this agreement, Lilly will provide clinical supply of Alimta for OncoMed’s ongoing Phase 2 DENALI trial.

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"This agreement with Lilly strengthens our efforts to investigate demcizumab as a key component alongside Alimta and platinum chemotherapy for the initial treatment of locally advanced or metastatic non-squamous non-small cell lung cancer," said Paul J. Hastings, OncoMed’s Chairman and Chief Executive Officer. "These data will add to the growing body of research to determine whether certain three-drug combinations may help improve patient outcomes."

OncoMed initiated enrollment in the randomized Phase 2 DENALI trial in January 2015 to test the efficacy and safety of demcizumab in combination with Alimta and carboplatin. Alimta is approved as an initial treatment in combination with cisplatin for locally advanced or metastatic NSCLC for patients with non-squamous histology. The DENALI trial is expected to enroll approximately 200 patients with first-line metastatic Stage IV non-squamous NSCLC whose tumors do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation.

About Non-Small Cell Lung Cancer

According to the American Cancer Society, lung cancer (both small cell and non-small cell) is the second most common cancer in men and women and is by far the leading cause of cancer death. Non-small cell lung cancer is expected to make up the vast majority of the 224,210 newly diagnosed cancer cases and the 159,260 cancer deaths estimated to occur in the U.S. in 20141. Forty percent of patients with newly diagnosed non-small cell lung cancer have Stage IV disease.

About Demcizumab (anti-DLL4, OMP-21M18)

Demcizumab is a humanized monoclonal antibody that inhibits Delta-Like Ligand 4 (DLL4) in the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing CSC frequency, disrupting angiogenesis in the tumor and potentially augmenting anti-tumor immune response.

OncoMed has completed enrollment of two Phase 1b clinical studies of demcizumab plus standard-of-care in patients with first-line advanced pancreatic cancer and extensive stage non-squamous non-small cell lung cancer. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing. Data of the Phase 1b studies of demcizumab in pancreatic cancer and NSCLC were presented in September 2014 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, Spain. These data showed that demcizumab was well tolerated in combination with standard-of-care therapies and use of a truncated dosing regimen appeared to successfully mitigate risks of moderate-to-severe cardiopulmonary toxicities. In both Phase 1b studies, demcizumab demonstrated encouraging anti-tumor response rates.

Demcizumab is part of OncoMed’s collaboration with Celgene Corporation.

About ALIMTA (pemetrexed for injection)

In 2004, ALIMTA received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the second-line treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy treatment.

In 2008, ALIMTA, in combination with cisplatin, was approved as a first-line treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of the first-line approval, the FDA also approved a change to the second-line indication. ALIMTA is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior chemotherapy.

In 2009, ALIMTA was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

In 2012, ALIMTA was approved by the FDA as a continuation maintenance therapy for locally-advanced or metastatic NSCLC, following first-line therapy with ALIMTA plus cisplatin in patients with a nonsquamous histology.

ALIMTA is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Important Safety Information for ALIMTA (pemetrexed for injection)

What is the most important information that I should know about ALIMTA?

ALIMTA can suppress bone marrow function, which may cause low blood cell counts.

ALIMTA may not be appropriate for some patients.

If you are allergic to ALIMTA, tell your doctor because you should not receive it.

If you have liver or kidney problems, be sure to tell your doctor. Your dose of ALIMTA may have to be changed, or ALIMTA may not be right for you.

It is very important to take the following medications prior to and during your treatment with ALIMTA to lower your chances of harmful side effects:

You must take folic acid every day by mouth beginning 7 days before your first dose of ALIMTA. You must keep taking folic acid every day during the time you are being treated with ALIMTA, and every day for 21 days after you receive your last dose of ALIMTA.

Your doctor will give you vitamin B12 injections while you are getting treatment with ALIMTA. You will get your first vitamin B12 injection one week before your first dose of ALIMTA, and then about every 9 weeks during treatment.

Your doctor will prescribe a medicine called a "corticosteroid" which you must take the day before, the day of, and the day after each treatment with ALIMTA to reduce rash.

You will have regular blood tests before and during your treatment with ALIMTA. Your doctor may adjust your dose of ALIMTA or delay your treatment based on the results of your blood test and on your general condition.

What should I tell my doctor before receiving ALIMTA?

If you think you are pregnant, are planning to become pregnant, or are nursing, please tell your healthcare team. ALIMTA may harm your unborn or nursing baby. Your physician may advise you to use effective contraception (birth control) to prevent pregnancy while you are being treated with ALIMTA.

Tell your doctor if you are taking other medicines, including prescription and nonprescription medicines, vitamins, and herbal supplements. ALIMTA and other medicines may affect each other, causing serious side effects. Especially, tell your doctor if you are taking medicines called "nonsteroidal anti-inflammatory drugs" (NSAIDs) for pain or swelling.

What are the possible side effects of ALIMTA?

Most patients taking ALIMTA will have side effects. Sometimes it is not always possible to tell whether ALIMTA, another medicine, or the cancer itself is causing these side effects.

Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. These symptoms could mean you have an infection, which may be severe and could lead to death.

The most common side effects of ALIMTA when given alone or in combination with cisplatin are:

Stomach upset, including nausea, vomiting, diarrhea, or constipation. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms.

Low blood cell counts:
Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appear pale, and become short of breath.
Low white blood cells. Low white blood cells may give you a greater chance for infection. If you have a fever (temperature above 100.4°F) or other signs of infection, call your doctor right away.
Low platelets. Low platelets give you a greater chance for bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with ALIMTA.

Tiredness. You may feel tired or weak for a few days after your ALIMTA treatments. If you have severe weakness or tiredness, call your doctor.

Redness or sores in your mouth, throat, on your lips or in the tube that connects your throat and stomach (esophagus). You may get redness or sores in your mouth, throat, on your lips, or in your esophagus (stomatitis, pharyngitis, esophagitis) or you may feel pain or have difficulty when drinking or swallowing food. These symptoms may happen a few days after ALIMTA treatment. Talk with your doctor if you get any of these symptoms.

Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.

Rash. You may get a rash or itching during treatment. These reactions usually appear between treatments with ALIMTA and usually go away before the next treatment. Skin reactions or rashes that include blistering or peeling may be severe and could lead to death. Call your doctor if you have any of these symptoms.

Talk with your doctor, nurse, or pharmacist about any side effect that bothers you or that doesn’t go away.

These are not all the side effects of ALIMTA. For more information, ask your doctor, nurse, or pharmacist.

How is ALIMTA given?

ALIMTA is slowly infused (injected) into a vein. The injection or infusion will last about 10 minutes. You will usually receive ALIMTA once every 21 days (3 weeks).

For more information about all of the side effects of ALIMTA, please talk with your healthcare team, see the Patient Prescribing Information, View Source, Prescribing Information, View Source, visit www.ALIMTA.com, or call 1-800-545-5979.

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 April 2, 2015 Medivation and Astellas Pharma reported topline results from the Phase 2 STRIVE trial comparing enzalutamide with bicalutamide in a study population of men with non-metastatic or metastatic castration-resistant prostate cancer (Press release, Medivation, APR 2, 2015, View Source [SID:1234502908]). The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared with bicalutamide (Hazard Ratio = 0.24; 95% Confidence Interval, 0.18-0.32; p < 0.0001). Median PFS was 19.4 months in the enzalutamide group compared with 5.7 months in the bicalutamide group. The median time on treatment in the STRIVE trial was 14.7 months in the enzalutamide group versus 8.4 months in the bicalutamide group. Serious adverse events were reported in 29.4% of enzalutamide-treated patients and 28.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.1% of enzalutamide-treated patients versus 4.0% of bicalutamide-treated patients. One seizure was reported in the trial in the enzalutamide-treated group and none in the bicalutamide-treated group. The most common side effects noted more frequently in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, back pain, hot flush, fall, hypertension, dizziness, and decreased appetite, consistent with the known safety profile of enzalutamide. "These results demonstrate the potential for enzalutamide to provide a longer duration of disease control compared with bicalutamide in the studied patient population," said David Penson, M.D., MPH, co-principal investigator of the STRIVE study, Director of the Center for Surgical Quality and Outcomes Research and Chair of the Department of Urologic Surgery of Vanderbilt University Medical Center. The STRIVE study is the second of two head-to-head studies of enzalutamide versus bicalutamide, the first of which was TERRAIN. Additional results from the STRIVE trial, including the secondary endpoints and safety data, will be submitted for presentation at upcoming medical conferences. About STRIVE The Phase 2 STRIVE trial enrolled 396 castration-resistant prostate cancer patients in the United States. The trial randomized 257 patients with metastatic prostate cancer and 139 patients with non-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 progression-free survival, defined as time from randomization to radiographic (bone or soft tissue) progression, PSA progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with a LHRH analogue. About TERRAIN The Phase 2 TERRAIN trial enrolled 375 patients in North America and Europe. The trial randomized 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 progression-free survival, defined as time from randomization to centrally confirmed radiographic progression, skeletal related event, initiation of new anti-neoplastic therapy or death, whichever occurs first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with a 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 three different steps in the androgen receptor signaling pathway. Important Safety Information (from currently approved U.S. prescribing information) Contraindications: XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions: In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re‐administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas 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. Adverse Reactions: The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated 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. Other Adverse Reactions include: Laboratory Abnormalities: In the two studies, Grade 1‐4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1‐4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls: In the two studies, falls including fall‐related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. 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: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients. Drug Interactions: Effect of Other Drugs on XTANDI ‐ Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co‐administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co‐administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co‐administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs ‐XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. 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/PI