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JOINT PROMOTION AGREEMENT ON ANTIEMETIC AGENT WITH HELSINN THERAPEUTICS INC. IN THE UNITED STATES REVISED Eisai to Return All Rights to Promote and Distribute AKYNZEO(R) (netupitant/palonosetron) to Helsinn Therapeutics Inc.

On March 22, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its U.S. subsidiary Eisai Inc. has agreed to revise the joint promotion agreement with Helsinn Healthcare S.A. (Headquarters: Lugano, Switzerland, Group Vice Chairman and CEO: Riccardo Braglia, "Helsinn") for their chemotherapy-induced nausea and vomiting (CINV) franchise (Press release, Eisai, MAR 22, 2016, View Source [SID:1234509811]).

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Under the new arrangement, from April 1, 2016, Helsinn Therapeutics Inc., the U.S. affiliate of Helsinn ("Helsinn U.S."), will obtain exclusive rights to promote and sell AKYNZEO (netupitant/palonsetron), its oral fixed dose combination product for the prevention of CINV. AKYNZEO had previously been co-promoted in the United States by both Helsinn U.S. and Eisai Inc. As part of the revised agreement, Eisai and Helsinn U.S. will continue to co-promote ALOXI (palonosetron HCl) injection in the United States for CINV.

Moving forward, Eisai Inc. will focus on further contributing to patients with ALOXI through this revised joint promotion agreement with Helsinn U.S., along with Eisai’s in-house anticancer agents Halaven and Lenvima.

1. About AKYNZEO
AKYNZEO is a new oral fixed combination that targets two critical signaling pathways associated with CINV, by combining netupitant, an NK1 receptor antagonist, with palonosetron, a 5-HT3 receptor antagonist. Marketing authorization applications for AKYNZEO are currently being submitted in countries throughout the world.

20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

(Filing, Annual, Cellectis, 2015, MAR 21, 2016, View Source [SID:1234509777])

Survival Results with Advaxis HER2 Targeted Immunotherapy in Canine Osteosarcoma Published in Clinical Cancer Research

On March 21, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported that data from a dose-escalation study of ADXS-HER2 in canine osteosarcoma (OSA) was published online March 18, 2016 in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Advaxis, MAR 21, 2016, View Source [SID:1234510047]).

The study by Nicola Mason, PhD, BVetMed, Associate Professor of Medicine at the University of Pennsylvania School of Veterinary Medicine, evaluated the immunogenicity, safety, and impact of attenuated, recombinant Listeria monocytogenes (Lm) transformed with a HER2/Neu fusion protein (ADXS-HER2) on survival in 18 dogs with surgically treated osteosarcoma. The research is part of Advaxis’ ongoing ADXS-HER2 clinical program.

"This is promising and important research both for dogs and humans," said Dr. Mason. "We were able to use the Advaxis Lm Technology to induce an antigen-specific T-cell response against HER2/Neu which is expressed in both canine and pediatric osteosarcoma, with only low-grade, transient side-effects. I am very excited about these results and the potential this technology holds for treatment of cancer patients of either species."

In the study, 18 dogs received either 2×108, 5×108, 1×109 or 3.3×109 CFU of ADXS–HER2 post-completion of surgery and adjuvant chemotherapy with 15 dogs showing an induced antigen-specific response within 6 months of immunotherapy administration. Additionally, treatment with ADXS-HER2 reduced the incidence of metastatic disease and prolonged survival relative to a historical control group. The median survival time for the ADXS-HER2 treated dogs was 956 days which was significantly longer than the 423 day median survival time of the historical control group (p=0.014, HR 0.33; 95% CI 0.136-0.802).

Osteosarcoma is the most common primary bone tumor in dogs, with more than 10,000 dogs annually diagnosed. Osteosarcoma is also the most common bone cancer in children and teens. It is the third most common cancer in teens after lymphomas and brain tumors. HER2 is expressed in approximately 40 to 60 percent of pediatric and canine osteosarcomas and in pulmonary metastatic disease, providing strong rationale for HER2 targeted immunotherapy in these cancers.

About ADXS-HER2

ADXS-HER2 is an Lm Technology immunotherapy product candidate being developed by Advaxis to target HER2 expressing cancers. ADXS-HER2 has received orphan drug designation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of osteosarcoma. Advaxis is developing ADXS-HER2 for both human and animal health, and has seen encouraging data in canine osteosarcoma, which is considered a model for human osteosarcoma. Advaxis has licensed ADXS-HER2 to Aratana Therapeutics, Inc. for animal health therapeutics. Aratana expects to receive a conditional USDA license by the end of 2016 to market and sell ADXS-HER2 for dogs with canine osteosarcoma.

Janssen Announces the Initiation of Two Studies Evaluating Daratumumab (DARZALEX®) and Atezolizumab in Multiple Myeloma and Solid Tumor

On March 21, 2016 Janssen Research & Development, LLC reported it has entered into a clinical trial collaboration agreement with Genentech, a member of the Roche Group, to initiate two studies to determine the safety and tolerability of daratumumab (DARZALEX), the first CD38-directed monoclonal antibody (mAb), in combination with atezolizumab, an investigational mAb designed to bind with a protein called programmed cell death-ligand 1 (PD-L1) (Press release, Johnson & Johnson, MAR 21, 2016, View Source [SID:1234509812]). These studies will assess the potential of the combination therapy in multiple myeloma and in solid tumor. Atezolizumab is currently in development by Roche. Janssen licensed daratumumab from Genmab A/S and is responsible for development and marketing.

As part of the collaboration, Janssen will sponsor a Phase 1b, open-label, multicenter study that will investigate the potential of daratumumab in combination with atezolizumab in patients with solid tumor. Genentech is the sponsor of an ongoing Phase 1b, open-label, multicenter study that will be amended to assess atezolizumab in combination with daratumumab, with daratumumab and lenalidomide, and with daratumumab and pomalidomide in patients with relapsed or refractory multiple myeloma. These studies are anticipated to start dosing patients within a year.

"We are excited to see if the immunomodulatory properties of daratumumab may have synergistic treatment effects when used in combination with this promising anti-PDL1 antibody," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development. "This is the first time we’re exploring daratumumab in solid tumor, and we look forward to better understanding how combining these two immunotherapies may potentially benefit patients with multiple myeloma and solid tumor, who are urgently in need of new options."

In November 2015, DARZALEX was approved by the U.S. Food and Drug Administration for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed monoclonal antibody (mAb) approved anywhere in the world.1 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.2 Daratumumab is believed to induce tumor cell death through apoptosis, in which a series of molecular steps in a cell lead to its death1,3 as well as immunomodulatory effects and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).1,4,5 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma. DARZALEX is the first mAb to receive regulatory approval to treat relapsed or refractory multiple myeloma.1

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX. DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc.6

DARZALEX (daratumumab) Important Safety Information – Professional
CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence =20%) were: fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection.

Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS – No drug interaction studies have been performed.

Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy.

High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality.