1stOncology™: Cancer Intelligence Service – Page 16478 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Puma Biotechnology Announces I-SPY 2 Phase II Study of Neratinib Published in The New England Journal of Medicine

On July 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that the positive results from the I-SPY 2 Phase II clinical trial of neratinib for the neoadjuvant treatment of breast cancer were published in the July 7 issue of The New England Journal of Medicine (Press release, Puma Biotechnology, JUL 7, 2016, View Source [SID:1234513761]).

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 I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) is a randomized Phase II clinical trial for women with newly diagnosed Stage 2 or higher (tumor size at least 2.5 cm) breast cancer that addresses whether adding investigational drugs to standard chemotherapy in the neoadjuvant setting is better than standard chemotherapy. The primary endpoint is pathological complete response (pCR) in the breast and the lymph nodes at the time of surgery. The goal of the trial is to match investigational regimens with patient subsets on the basis of molecular characteristics (referred to as biomarker signatures) that benefit from the regimen. The trial enrolled patients who had a high risk of relapse using up-front tumor profiling (including tumor size, hormone receptor status (HR), HER2 status, and the MammaPrint 70-gene signature test).

The I-SPY 2 TRIAL involves an adaptive trial design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard neoadjuvant therapy in an equally randomized 300-patient confirmatory trial. Regimens that have a high Bayesian predictive probability of showing superiority in at least one of 10 predefined signatures graduate from the trial. Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. A maximum total of 120 patients can be assigned to each experimental regimen. A regimen can graduate early and at any time after having 60 patients assigned to it.

The neratinib-containing regimen (neratinib plus paclitaxel followed by doxorubicin and cyclophosphamide) graduated from the I-SPY 2 TRIAL based on having a high probability of success in Phase III with a signature of HER2-positive/HR-negative. In this group, treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 55.6% compared to the control arm (standard neoadjuvant chemotherapy: paclitaxel in combination with Herceptin (trastuzumab) followed by doxorubicin and cyclophosphamide) which had an estimated pCR rate of 32.6%. The Bayesian probability of superiority for the neratinib-containing regimen (compared to standard therapy) is 94.9%, which is analogous to a one-sided p-value of 0.051. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab, both followed by doxorubicin/cyclophosphamide, is 79.1%.

There were 115 patients assigned to neratinib in the trial, including 65 patients who were HER2-positive. For the patients in the trial who were HER2-positive (including those who were either hormone receptor-positive or negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 39.4% compared to the control arm, which demonstrated an estimated pCR rate of 22.8%. The Bayesian probability of superiority for the neratinib-containing regimen is 95.4%, which is analogous to a p-value of 0.046. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab is 72.7%.

Patients in the I-SPY 2 TRIAL were screened using the MammaPrint 70-gene signature test. The median MammaPrint score from the patients in the previous I-SPY 1 TRIAL who fit the eligibility criteria for I-SPY2 was used as a predefined stratification factor for the I-SPY 2 TRIAL. Patients in I-SPY 2 were stratified as either MammaPrint High (below the median from I-SPY 1) or MammaPrint Ultra High (above the median from I-SPY 1). For the 41 neratinib treated patients in the trial who were MammaPrint Ultra High (80.5% of which were HER2 negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 47.5% compared to the control arm, which demonstrated an estimated pCR rate of 29.4%. The Bayesian probability of superiority for the neratinib-containing regimen is 93.3%, which is analogous to a p-value of 0.067. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel, alone for HER2-negative patients or in combination with trastuzumab for the HER2-positive patients, is 71.8%.

The most frequently observed severe adverse event in the trial was diarrhea. In the neratinib treated arm of the trial 38% of the patients experienced grade 3/4 diarrhea while 4% of the patients in the control arm experienced grade 3/4 diarrhea. In several clinical trials subsequent to I-SPY 2, high dose loperamide significantly reduced the incidence of grade 3/4 diarrhea.

The I-SPY 2 TRIAL is a collaborative effort among academic investigators from approximately 20 major cancer research centers across the country, the U.S. Food and Drug Administration, Quantum Leap Healthcare Collaborative, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium. Major supporters include The Safeway Foundation and the Bill Bowes Foundation.

"I-SPY 2 is an innovative adaptive clinical trial that enabled the investigators to evaluate several agents in the neoadjuvant setting," said Alan H. Auerbach, Chief Executive Officer and President. "We were very pleased with the activity of neratinib in I-SPY 2 as it represents the first clinical data on neratinib in the neoadjuvant treatment of breast cancer and suggests that the combination of paclitaxel plus neratinib has potent activity for the treatment of HER2-positive breast cancer and a subset of patients with HER2-negative breast cancer."

I-SPY 2 Principal Investigators Dr. Laura Esserman, Director of the Carol Franc Buck Breast Care Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, and Dr. Donald Berry, Professor of the Department of Biostatistics at the University of Texas MD Anderson Cancer Center, both expressed their enthusiasm for moving successful agents into confirmatory Phase 3 trials. "We are excited for the opportunity to confirm these promising results in I-SPY 3 in our quest to get better treatments to those women who stand to benefit most. I SPY 3 represents a much needed approach to the conduct of Phase 3 trials," said Laura Esserman.

European Data Supporting Survival Benefit With Delcath’s CHEMOSAT System Presented At 6th European Post-Chicago Melanoma/Skin Cancer Meeting

On July 6, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on treatment of primary and metastatic liver cancers, reported that data from a large single hospital experience conducted at Southampton University Hospital in the United Kingdom were presented in an oral presentation at the 6th European Post-Chicago Melanoma/Skin Cancer Meeting held in Munich, Germany from June 30 – July 1, 2016 (Press release, Delcath Systems, JUL 6, 2016, View Source;p=RssLanding&cat=news&id=2182241 [SID:1234513737]).

The abstract, Chemosaturation Via Percutaneous Hepatic Perfusion – An Update On A Single Centre Experience Of Treating Metastatic Uveal Melanoma, Southampton University (United Kingdom) was presented by lead author, Ioannis Karydis, M.D, of Southampton University Hospital. Researchers conducted a retrospective evaluation of 27 metastatic uveal melanoma patients treated with CHEMOSAT over four years, analyzing survival, tumor response, time to progression and treatment related adverse events. Two patients could not be treated and were excluded from analysis; 25 patients received 43 treatments. Results showed that 14 patients remained alive after a median 290 days. Of 24 evaluable patients, one patient had a complete response (4%), five patients had partial responses (21%), and 12 patients had stable disease for greater than 90 days (50%). Progression free survival for patients who had progressed was 181 days at the time of data cut off, and 11 patients were alive for greater than one year following their first treatment with a projected media overall survival of 511 days. Eleven deaths from disease progression occurred at a median of 264 days following first treatment, and there were no treatment related deaths. Treatment overall was well tolerated, and non-hematological adverse events (6) were relatively rare. Most common adverse events were transient, mild

Researchers concluded that "PHP can be used safely by an experienced team to deliver liver-directed therapy in selected uveal melanoma patients, and achieves unprecedented progression free and overall survival."

"The progression free and overall survival benefits observed in this study are dramatic, especially given the limited treatment options for patients suffering with these life-threatening cancers. Importantly, these supportive data provide us with considerable confidence that similar results may be formally validated by our FOCUS Phase 3 Trial in hepatic dominant ocular melanoma that is currently underway in the U.S. and Europe to secure marketing authorization in the U.S.," said Jennifer K. Simpson, Ph.D., MSN, CRNP, President and CEO of Delcath Systems. "The quality and pace of global research being presented and published continues to strongly support CHEMOSAT as a therapy for metastatic liver cancer. We look forward to building on this momentum to further advance the commercial and clinical adoption of CHEMOSAT in Europe, the U.S. and around the world."

Merck KGaA, Darmstadt, Germany, and Pfizer Initiate Phase III Trial to Evaluate Avelumab as First-line Treatment for Ovarian Cancer

On July 6, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) reported the initiation of a Phase III study, JAVELIN Ovarian 100 (NCT02718417), to evaluate the efficacy and safety of avelumab* in combination with, and/or as follow-on (maintenance) treatment to, platinum-based chemotherapy in patients with locally advanced or metastatic disease (Stage III or Stage IV) with previously untreated epithelial ovarian cancer (Press release, Pfizer, JUL 6, 2016, View Source [SID:1234513746]). JAVELIN Ovarian 100 is the first Phase III study evaluating the addition of an immune checkpoint inhibitor to standard-of-care in first-line treatment for this aggressive disease.

"In an early ongoing study, avelumab showed encouraging tumor response rates in patients with recurrent or refractory ovarian cancer," said Alise Reicin, M.D., Head of Global Clinical Development at the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "Historically, ovarian cancer presents as an advanced disease with poor survival rates. The hope is that avelumab can change the natural history of the disease and potentially take the survival rate beyond the current five year estimate."

JAVELIN Ovarian 100 is an open-label, international, multi-center, randomized (1:1:1) Phase III trial in treatment naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). This study is designed to evaluate the potential superiority of two first-line therapies with avelumab and platinum-based chemotherapy versus platinum-based chemotherapy alone, as assessed by progression-free survival. The study will enroll approximately 950 patients, who will receive concurrent avelumab and chemotherapy, avelumab following chemotherapy, or chemotherapy alone.

"Patients with ovarian cancer need additional treatment options. We believe there could be synergistic activity in the combination of avelumab and established treatments such as platinum-based chemotherapy," said Chris Boshoff, M.D., Ph.D., Head of Early Development, Translational and Immuno-Oncology, Oncology in Pfizer Global Product Development. "With two studies now underway of avelumab in ovarian cancer, we look forward to receiving the results from these trials and continuing to break ground in this hard-to-treat cancer."

The alliance aims to build a strong foundation in ovarian cancer. In December 2015, Merck KGaA, Darmstadt, Germany, and Pfizer announced the initiation of an international Phase III study of avelumab as a treatment for platinum-resistant/refractory ovarian cancer. As of May 2016, the complete JAVELIN clinical development program for avelumab includes approximately 2,200 patients enrolled, being treated across more than 15 tumor types.

For more information about avelumab, please visit www.powerofcombination.com (link is external).

*Avelumab is the proposed nonproprietary name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

References

1. GLOBOCAN2012. International Agency for Research on Cancer. World Health Organization. View Source (link is external). Last accessed June 1, 2016.

2. Ovarian Cancer Statistics. World Cancer Research Fund International. View Source (link is external). Last accessed June 1, 2016.

About Ovarian Cancer

Ovarian cancer causes more deaths than any other gynecologic cancer globally. Each year, nearly a quarter of a million women will be diagnosed with ovarian cancer worldwide.1 Women in Europe and Northern America have the highest incidence rates of ovarian cancer.2 Patients are said to have ‘platinum-resistant’ disease if the disease worsens within 6 months of completing platinum-based chemotherapy. One quarter of those who relapse after initial treatment, more than 4,300 women, will have platinum-resistant cancer, the most difficult-to-treat form of the disease.

About Avelumab

Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Evotec enters license agreement for access to CRISPR-Cas9 gene editing technology

On July 6, 2016 Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX, ISIN: DE0005664809) reported that the Company has entered into a non-exclusive licence agreement with the Broad Institute of MIT and Harvard for the use of CRISPR-Cas9 gene editing technology (Press release, Evotec, JUL 6, 2016, View Source [SID:1234513728]).

Under the terms of this research tool licence, Evotec gains access to IP related to CRISPR-Cas9 and will apply the technology to its drug discovery offerings and R&D activities, especially for the development of research tools and in target identification, and to further strengthen its post phenotypical screening target deconvolution platform.

With this agreement, Evotec obtains non-exclusive access to the leading technology on the market for gene editing.

Dr Mario Polywka, Chief Operating Officer of Evotec, commented: "Alongside Evotec’s comprehensive stem cell capabilities, the ability to offer CRISPR-Cas9 research tools emphasises the Company’s continuing approach to establishing cutting-edge technologies for the benefit of our partners and growing R&D pipeline."

ABOUT THE CRISPR-CAS9 SYSTEM
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a naturally-occurring bacterial immune system. Researchers have harnessed this system as a genome editing tool for mammalian cells. The CRISPR-Cas9 gene editing system allows researchers to target specific genes, to mutate these and achieve knock out or enhance the expression of these in living cells. Through application of the CRISPR-Cas9 technology, valuable insights into the functions of these genes in disease establishment and progression can be gained.

FDA Grants Merrimack Fast Track Designation for Seribantumab (MM-121) in Non-small Cell Lung Cancer

On July 6, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported that the U.S. Food and Drug Administration (FDA) has granted seribantumab, also known as MM-121, Fast Track designation for development in patients with heregulin-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed following immunotherapy (Press release, Merrimack, JUL 6, 2016, View Source [SID:1234513745]). Fast Track is a program designed by the FDA to facilitate and expedite the development and review of drugs that treat serious conditions and fill an unmet medical need. Merrimack is conducting the SHERLOC trial, a global clinical study of seribantumab in combination with docetaxel or pemetrexed in heregulin-positive patients with NSCLC that is designed to support a Biologics License Application to the FDA. Seribantumab is Merrimack’s wholly owned, fully human monoclonal antibody that targets ErbB3.

"We are pleased that the FDA recognizes the importance of investigating a novel, biomarker-directed agent such as seribantumab for patients with locally advanced or metastatic NSCLC who have been previously treated with an immunotherapy," said Dr. Akos Czibere, Vice President, Clinical Development at Merrimack. "Heregulin-positive cancer cells are characterized by their ability to escape the effects of a broad range of cancer therapies and potentially contribute to accelerated disease progression. The SHERLOC trial is designed to advance the development of a much-needed treatment option for patients with heregulin-positive NSCLC after they progress on immunotherapies. This is important because we find that more than 50% of patients with NSCLC are heregulin-positive."

Heregulin-positive disease has been linked to rapid progression and poor prognosis in multiple types of cancer, including NSCLC. The higher the prevalence of heregulin-positive cancer cells in a tumor, the lower the anti-tumor effect of the chemotherapy. Seribantumab is designed to block heregulin-driven signaling and enhance the anti-tumor effect of the chemotherapy. Data from Merrimack’s prior clinical studies have shown that standard-of-care therapy may be more effective and result in improved patient outcomes when combined with seribantumab. Merrimack is investigating the efficacy and safety of seribantumab plus standard-of-care therapy in the SHERLOC trial.

Lung cancer is the leading cause of cancer-related death in the United States. The American Cancer Society estimates that approximately 224,000 new cases of lung cancer (both small cell lung cancer and NSCLC) will be reported in 2016, 83% of which will be NSCLCi. Merrimack estimates that approximately 101,000 U.S. NSCLC patients will have heregulin-positive tumors, based on the prevalence seen in data presented by Merrimack at the 2014 European Society for Medical Oncology Congressii.

About the SHERLOC Trial

The SHERLOC trial is a randomized, open-label, multi-center, Phase 2 study in patients with heregulin-positive, locally advanced or metastatic NSCLC. Merrimack expects to enroll approximately 280 heregulin-positive patients who will be randomized (2:1) to receive seribantumab in combination with either docetaxel or pemetrexed versus docetaxel or pemetrexed alone. Patients will be screened for heregulin status using a fully validated RNA-ISH assay (in situ hybridization). Eligible patients for the study must have failed prior treatment with no more than three lines of therapy including prior anti-PD-1 or anti-PD-L1 immunotherapy. The study’s primary endpoint is overall survival with secondary endpoints including progression free survival, objective response rate, safety and quality of life measures. The study is designed to support a Biologics License Application to the FDA with data expected in 2018. For more information on this trial, please visit www.clinicaltrials.gov (Identifier: NCT02387216).

About Seribantumab (MM-121)

Seribantumab is Merrimack’s wholly owned, fully human anti-ErbB3 monoclonal antibody that targets phenotypically distinct heregulin-positive cancer cells within solid tumors. Heregulin-positive cancer cells are characterized by their ability to escape the effects of targeted, cytotoxic and anti-endocrine therapies and potentially contribute to rapid clinical progression in patients whose tumor cells test positive for heregulin as detected by RNA-ISH. When used in the combination setting, seribantumab is designed to block the heregulin/ErbB3 signaling axis in order to make these cells accessible to the effects of the combination therapy and potentially lead to significantly improved clinical outcomes.

Merrimack is also developing its novel heregulin assay for seribantumab into a kit for commercial use under a partnership agreement with Leica Biosystems.