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Daiichi Sankyo and ArQule Announce Continuation of METIV-HCC Phase 3 Study of Tivantinib in Second-Line Hepatocellular Carcinoma

On March 22, 2016 ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo reported that the independent data monitoring committee (DMC) of the METIV-HCC study conducted the planned interim assessment and it was determined the trial will continue to its final analysis (Press release, ArQule, MAR 22, 2016, View Source [SID:1234509818]).

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METIV-HCC is a biomarker-selected, double-blind, placebo-controlled, pivotal phase 3 study evaluating tivantinib (2:1) versus best supportive care in previously systemically-treated patients with MET-high, inoperable HCC, with overall survival as the primary endpoint.

The interim analysis was triggered when at least 60 percent of the target number of events occurred. The final analysis will take place when 100 percent of the target number of events occurs. The METIV-HCC trial completed patient accrual in December 2015 with more than 300 patients with MET-high HCC enrolled.

About Hepatocellular Carcinoma (HCC)
Liver cancer is the sixth most common cancer globally with 782,000 new cases in 2012 and is the second most common cause of cancer-related death with 745,000 deaths in 2012.1 HCC accounts for about 90 percent of primary liver cancers.2 Cirrhosis, chronic hepatitis B and C and smoking are recognized worldwide as factors increasing the risk of HCC.2

About MET and Tivantinib (ARQ 197)
Tivantinib is an oral MET inhibitor, currently in phase 2 and phase 3 clinical trials. In healthy adult cells, MET can be present in normal levels to support natural cellular function, but in cancer cells, MET can be inappropriately and continuously activated. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signaling pathways, including MET, has also been associated with the development of resistance to anti-EGFR (epidermal growth factor receptor) antibodies such as cetuximab and panitumumab.

In clinical trials to date, treatment with tivantinib has been generally well tolerated and has shown clinical activity in a number of tumors studied. Tivantinib has not yet been approved for any indication in any country.

In December 2008, ArQule and Daiichi Sankyo signed a licensing, co-development and cocommercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan. 2 In November 2015, ArQule exercised its co-commercialization option for tivantinib in the U.S. A co-commercialization agreement is expected to be finalized in 2016.

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]).

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.