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Preclinical Research Demonstrates Peregrine Pharmaceuticals’ PS-Targeting Antibodies Enhance the Anti-Tumor Activity of PD-L1 Checkpoint Inhibitors in Model of Triple Negative Breast Cancer (TNBC)

On October 24, 2016 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, reported the presentation of preclinical study data demonstrating that phosphatidylserine (PS)-targeting antibodies similar to bavituximab are able to enhance the anti-tumor activity of anti-PD-L1 therapy in a model of triple negative breast cancer (TNBC) (Press release, Peregrine Pharmaceuticals, OCT 24, 2016, View Source [SID1234515967]). Data showed that a combination of anti-PS and anti-PD-L1 therapies, with or without paclitaxel, led to greater anti-tumor responses than any of the treatments administered as single agents or dual treatment combinations with paclitaxel, in the well-characterized E0771 murine model of TNBC. Study results were presented by researchers from Duke University Medical Center at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s Tumor Immunology and Immunotherapy Conference held October 20-23, 2016 in Boston, MA.

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In addition to evaluating the anti-tumor activity of the various treatment combinations, researchers also examined the impact of various traditional cancer therapies on PS expression in cancer cells. Study results confirmed that levels of PS expression were upregulated in E0771 and 4T1 TNBC cells following treatment with chemotherapy, radiation or photodynamic therapy. Photodynamic therapy also was shown to increase PS expression on tumor cells.

"These study results provide the latest support for the belief that PS-targeting therapies can enhance the anti-tumor activity of checkpoint inhibitors such as anti-PD-L1 therapy in the treatment of TNBC. Just last month, we announced results from another preclinical study in TNBC demonstrating that 80% of animals receiving the triple combination of anti-PS, anti-PD-1 and anti-LAG3 therapies experienced complete tumor regressions, whereas there were no animals in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression," said Jeff T. Hutchins, Ph.D., Peregrine’s vice president, preclinical research. "Additionally, these latest study findings related to increased PS expression on the surface of tumor cells following traditional cancer treatments demonstrate important activity within the tumor microenvironment that offers rationale for the potential of anti-PS agents in combatting cancer. We plan to continue to work with our collaborators at Duke University Medical Center to further study the therapeutic potential of PS-targeting agents in combination with checkpoint inhibitors like anti-PD-L1 and conventional therapies that augment immunotherapy mechanisms."

Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine evaluates the preclinical equivalent of bavituximab, ch1N11, in animal model studies to guide clinical development.

Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations. Those trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab’s combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.

Advaxis Announces GOG-0265 12-month Overall Survival Rate of 37.5% in Stage 2

On October 24, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported topline results from the early closure of stage 2 of the Phase 2 GOG-0265 trial, conducted by the Gynecologic Oncology Group (GOG, now part of NRG Oncology) and supported by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) (Press release, Advaxis, OCT 24, 2016, View Source [SID1234515966]).

GOG-0265 is a single-arm, open-label Phase 2 multicenter study (NCT01266460) designed to evaluate the safety and activity of axalimogene filolisbac in patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) in a standard Simon two-stage design. The first stage of the study included a six-patient safety run-in and enrolled 26 patients. The first stage of the study was previously completed, meeting the predetermined safety and efficacy criteria required to proceed into the second stage of patient enrollment. The second stage enrolled 24 patients prior to the clinical hold that affected Advaxis’ clinical development programs last year. The second stage was not completed as designed due to the clinical hold.

A preliminary analysis of 12-month overall survival data from 24 patients enrolled in the second stage prior to the clinical hold showed that treatment with axalimogene filolisbac resulted in a 37.5 percent 12-month overall survival rate. These preliminary findings are consistent with earlier data that showed a 38.5 percent 12-month overall survival rate in 26 patients enrolled in the first stage of the study, despite modest differences in dosing schedules between the two stages.

Based on protocol defined prognostic factors of patients who enrolled in the study (n=50), a 12-month survival rate of 25 percent would have been expected. Comparing this 25 percent 12-month overall survival rate to the 38 percent 12-month overall survival rate actually observed across the total study population, treatment with axalimogene filolisbac resulted in a 52 percent increase in the expected 12-month overall survival rate.

"These data demonstrate a meaningful improvement in 12-month overall survival rate compared to historical GOG studies," said Warner K. Huh, M.D., division director of Gynecologic Oncology at the University of Alabama at Birmingham, and lead investigator of the study. "Historical survival rates for patients with PRmCC underscore the need for additional treatment options for patients and these results illustrate the promising therapeutic potential for axalimogene filolisbac in women with this rare cancer."

In the second stage of the study, 15 out of 24 patients experienced a Grade 1 or Grade 2 treatment-related adverse event (TRAE). The most common Grade 1 or Grade 2 TRAEs were hypotension and symptoms related to cytokine release (e.g., nausea, chills, fever). Nine out of 24 patients experienced a Grade 3 TRAE and two out of 24 patients experienced a Grade 4 TRAE, which were hypotension and symptoms related to cytokine release.

"We are very encouraged by these data and look forward to presenting and discussing a more detailed analysis of the trial results at an upcoming medical society meeting," said Daniel J. O’Connor, president and chief executive officer of Advaxis. "We believe that a more than 50 percent increase in 12-month overall survival rate is clinically meaningful, and Advaxis plans to pursue registrational opportunities in Europe in 2017."

Axalimogene filolisbac was recently classified as an advance therapy medicinal product (ATMP) in the EU, has received U.S. Food and Drug Administration (FDA) Fast Track Designation as an adjuvant therapy for treating high risk, locally advanced cervical cancer (HRLACC), and has been granted U.S. orphan drug designation for the treatment of invasive cervical cancer.

About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide.2 An estimated 13,000 new cases will be diagnosed in the United States in 2016, and 4,100 people will die of the disease, according to the National Cancer Institute. Persistent HPV infection is the most important factor in the development of cervical cancer, research shows.3,4 According to the ICO Information Centre on HPV and Cervical Cancer, about 4.4 percent of women in the United States are estimated to harbor high-risk cervical HPV infection at a given time, and about 72 percent of cervical cancers are attributed to high-risk HPV strains.5 The prognosis for women with advanced and recurrent cervical cancer remains poor, with survival of only 4 to 7 months following failure of first-line treatment, research has shown.6. According to the American Cancer Society, the 5-year mortality rate for metastatic disease is at just 17 percent, with the area continuing to be a high unmet medical need.7

About The GOG Foundation, Inc.

The GOG Foundation, Inc. (GOG), now part of NRG Oncology, is a non-profit international organization with the purpose of promoting excellence in the quality and integrity of clinical and basic scientific research in the field of gynecologic malignancies. The GOG is committed to maintaining the highest standards in clinical trials development, execution, analysis and distribution of results. Continuous evaluation of its processes is utilized in order to constantly improve the quality of patient care. The GOG conducts clinical trials for patients with a variety of gynecologic malignancies, including cancers that arise from the ovaries, uterus, cervix, vagina and vulva. General information on many of these trials for medical professionals and the lay public can be obtained from ClinicalTrials.gov.

NRG Oncology is one of four adult US Network groups funded under the newly structured NCI National Clinical Trials Network. NRG Oncology is comprised of three legacy cooperative groups, the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG).

CEL-SCI PROVIDES UPDATE ON PARTIAL CLINICAL HOLD ON PHASE 3 CLINICAL TRIAL

On October 21, 2016 CEL-SCI Corporation (NYSE MKT: CVM) reported: following up on our press release issued on September 26, 2016, we have received the Partial Clinical Hold letter from the U.S. Food and Drug Administration (FDA) (Press release, Cel-Sci, OCT 21, 2016, View Source [SID1234515949]). CEL-SCI has started working on a response to the FDA and will work diligently with the FDA to seek to have the partial clinical hold lifted.

Myriad Genetics Inc. Forms Relationship with ION Solutions to Deliver Quality Hereditary Cancer Tests and Services to the Nation’s Largest Network of Community Oncologists

On October 21, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a global leader in personalized medicine, and ION Solutions, a part of AmerisourceBergen, and the largest physician services organization specializing in the support of community oncology, reported that they have entered into a relationship to deliver quality hereditary cancer test results and services to ION member practices (Press release, Myriad Genetics, OCT 21, 2016, View Source [SID1234515948]). Through this relationship, Myriad and ION will work together to enhance the operational and clinical value associated with hereditary cancer testing. Myriad will be ION’s preferred partner for hereditary cancer testing focused on bringing specialized tests and services to meet the specific needs of community oncology practices. This partnership will advance the organizations’ shared goals of providing accurate and comprehensive hereditary cancer test results and service to community oncologists and their patients.

"Myriad has demonstrated its commitment to quality with its significant investments in research, laboratory processes, variant interpretation and exceptional customer service," said Mark Santos, RPh, president of ION GPO. "This relationship supports ION Solutions in making important genetic tests available to our members in a way that will help inform treatment decisions and build patient care plans in the context of specific practice processes and objectives."

"ION Solutions is the industry leader in bringing effective business and clinical solutions to the largest segment of community oncology practices in the nation," said Alexander Ford, president of Myriad Genetic Laboratories, Inc. "Our focus as a company is on providing accurate, affordable and clinically significant genetic test results to providers and the patients they care for. We believe we share this commitment with ION Solutions and their members, and that through this partnership, the largest, most innovative private practices in the country will gain enhanced access to our services."

FDA Approves Supplemental New Drug Application for XTANDI® (enzalutamide) Capsules in Advanced Prostate Cancer

On October 21, 2016 Astellas Pharma Inc. (TSE: 4503) and Pfizer Inc. (NYSE: PFE (link is external)) reported that the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) to update the U.S. product labeling for XTANDI (enzalutamide) capsules to include new clinical data versus bicalutamide from the TERRAIN study (Press release, Pfizer, OCT 21, 2016, View Source [SID1234515947]). The data demonstrate improvement in radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (CRPC) who were treated with enzalutamide compared to patients who were treated with bicalutamide.

The TERRAIN study evaluated men with metastatic CRPC and the results from this study were published in the Lancet Oncology. The updated label includes data that enzalutamide reduces the risk of radiographic progression or death by 40% compared with bicalutamide, showing a median rPFS of 19.5 months for the enzalutamide group versus a median of 13.4 months for the bicalutamide group (hazard ratio = 0.60 [0.43, 0.83]; 95% confidence interval) based on an analysis recommended by the FDA. The safety profile of enzalutamide was consistent with results of earlier enzalutamide trials.

"The addition of data from the TERRAIN trial continues to build the body of evidence that demonstrates the clinical impact XTANDI can have for patients living with metastatic CRPC," said Steven Benner, M.D., senior vice president, therapeutic area head for oncology development, Astellas. "Advances in scientific knowledge as seen through clinical trials like TERRAIN would not be possible without the participation of hundreds of patients, family members and clinical investigators, and we thank them for their valuable contributions."

According to the American Cancer Society, each year approximately 181,000 new cases of prostate cancer will be diagnosed and an estimated 26,000 men will die of the disease in 2016.1 Up to 40 percent of men diagnosed with prostate cancer who undergo therapy develop metastatic, or advanced, prostate cancer.2 In the U.S., the five-year relative survival rate for prostate cancer patients with metastatic disease is 28 percent, compared with 100 percent for prostate cancer patients with non-metastatic disease.3

"We are pleased with the FDA’s decision to update the XTANDI label with these data from the first and largest comparative trial that demonstrated safety and efficacy of enzalutamide compared to bicalutamide," said Mohammad Hirmand, M.D., interim chief medical officer at Medivation, Inc., which is now part of Pfizer. "We believe these data will help physicians better understand the differences between enzalutamide and bicalutamide for their patients living with metastatic CRPC."

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion onApril 1, 2016 recommending approval of a type II variation to include data from the TERRAIN trials in the European label for XTANDI.

About the TERRAIN trial

The Phase II TERRAIN trial enrolled 375 chemotherapy-naïve patients with metastatic CRPC in North America and Europe. Radiographic progression-free survival was defined as the time from randomization to the first objective evidence of radiographic progression as assessed by Independent Central Review or death, whichever occurred first. The trial was designed to evaluate patients who were randomized 1:1 to receive enzalutamide at a dose of 160 mg taken orally once daily versus bicalutamide at a dose of 50 mg taken once daily.

Grade 3-4 adverse reactions were reported in 38.8% of enzalutamide-treated patients and 37.6% of bicalutamide-treated patients. Individual Grade 3 or higher adverse events largely occurred at a similar rate (<1% difference) between the enzalutamide vs. bicalutamide treatment groups, with the exception of hypertension (7.1% vs. 4.4%), diarrhea (0% vs. 1.1%) and back pain (2.7% vs. 1.6%). Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common Grade 1-4 adverse reactions (incidence ≥10%) occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included asthenic conditions, back pain, musculoskeletal pain, hot flush, hypertension, diarrhea, upper respiratory tract infection, and weight loss.

About XTANDI (enzalutamide) capsules

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 mechanism of action (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. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamide-controlled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. 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%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials 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 the bicalutamide-controlled study of chemotherapy naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

In the study of patients taking XTANDI who previously received docetaxel, 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 the placebo-controlled study of chemotherapy-naïve patients, 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. In the bicalutamide-controlled study of chemotherapy naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials 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 a study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the placebo-controlled study of chemotherapy-naïve patients, 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 in the two placebo-controlled trials. 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 in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients in each arm.

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.

Please see Full Prescribing Information (link is external) at View Source (link is external) for additional safety information.

You are encouraged to report negative side effects of prescription drugs to the FDA.

Visit www.fda.gov/medwatch (link is external) or call 1‐800‐FDA‐1088.