On November 20, 2018 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported scientific updates, including data from two ongoing clinical trials, at the 23rd Annual Meeting and Education Day of the Society for Neuro-Oncology (SNO) held on November 15-18, 2018 in New Orleans, LA (Press release, DelMar Pharmaceuticals, NOV 20, 2018, View Source [SID1234531494]).

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!

"In our much-awaited Phase 2 study of VAL-083 in patients with MGMT-unmethylated, Bevacizumab-Naïve Recurrent Glioblastoma Multiforme (rGBM), we are pleased with the accelerated enrollment of this study with the vast majority of subjects already enrolled. What has become amply clear is that in ‎this aggressive tumor type, which can double in size every 6-8 weeks, VAL-083 when used for two or more cycles can stabilize the tumor and slow down its incessant growth," commented Saiid Zarrabian, President and Chief Executive Officer.

"At this time, some subjects are still on drug and others are being followed for survival and we wait to see if this observed stabilization of the tumor favorably impacts median overall survival. The preclinical and clinical efficacy of VAL-083 in MGMT-unmethylated GBM population, along with the 2017 revised NCCN guidelines for MGMT-unmethylated patients which cautions against the use of temozolomide for MGMT-unmethylated GBM patients, creates a therapeutic opportunity not only for newly diagnosed patients, but also in the follow-on maintenance setting currently using temozolomide, all of which signals a path forward for VAL-083," added Mr. Zarrabian.

At the SNO 2018 conference, DelMar provided an update on the company’s ongoing Phase 2 clinical study in a poster entitled "Phase 2 Study of Dianhydrogalactitol (VAL-083) in Patients with MGMT-unmethylated, Bevacizumab-Naïve Recurrent Glioblastoma." This study is being conducted in collaboration with The University of Texas MD Anderson Cancer Center (MDACC). This biomarker-driven trial (testing for MGMT methylation status) is designed to enroll up to 48 patients to determine if VAL-083 treatment improves overall survival compared to historical reference control of 7.15 months with lomustine.

As of October 31, 2018, 44 (of 48) patients have been enrolled
41 of those enrolled have received at least 1 cycle of VAL-083
7 patients are currently receiving treatment; 22 being followed for survival; 19 deceased thus far
Study subjects received a median of 2 cycles of therapy
12 patients received only 1 cycle of VAL-083
2 patients received 1 cycle and are ongoing
27 patients completed 2 or more cycles of therapy
Of the 27 subjects that completed at least 2 cycles of treatment, 9/27 (33.33%) subjects exhibited stable disease (SD) at the end of cycle 2
8/23 initially receiving 40 mg/m2 exhibited SD at the end of cycle 2
1/4 initially receiving 30 mg/m2 exhibited SD at the end of cycle 2
The most prevalent side effect with the 40 mg/m2/day dose of VAL-083 was myelosuppression (thrombocytopenia and neutropenia)
Myelosuppression was also correlated with prolonged (> 5 cycles) prior front-line temozolomide use
in such patients a VAL-083 dose reduction to 30 mg/m2 was found optimal
The Company also provided an update on its Phase 1/2 clinical study in a poster entitled "Phase I/II Study of Dianhydrogalactitol (VAL-083) with Radiation Therapy with Newly Diagnosed MGMT-unmethylated Glioblastoma." This trial is being conducted at the Sun Yat-sen University Cancer Center (SYSUCC) in Guangzhou, China in collaboration with Guangxi Wuzhou Pharmaceutical Company. The trial is designed to enroll up to 30 patients to determine if first-line therapy with VAL-083 treatment, in lieu of first-line temozolomide, improves progression free survival (PFS).

As per the 2017 National Comprehensive Cancer Network (NCCN) guidelines, this trial sets out with the vision of eradicating the unnecessary use of temozolomide in the approximately 60% of GBM patients, as noted in prior studies, with unmethylated MGMT gene promoter
The Company reported that 10 patients have been enrolled as of October 31, 2018
These 10 patients were part of the "3+3" dose escalation cohorts, and were treated with VAL-083 at each different dose on days 1 to 3 of a 21-day cycle along with radiation at 2Gy/day x 5 days for 6 weeks. The same dosing regimen of VAL-083 would be applied during the maintenance stage following six-week chemo-radiation
In the dose-escalation stage, grade 3+ myelosuppression was observed in 2 of 3 patients treated with VAL-083 at 40 mg/m2/day
The lower VAL-083 dose of 30 mg/m2/day was hence moved forward into the expansion phase of the trial
A 20-patient expansion cohort has now commenced enrolling
The primary endpoint of this trial is progression free survival and secondary endpoints include tumor response, overall survival and pharmacokinetics
In addition, DelMar presented three preclinical updates during the conference:

VAL-083 Inhibits Proliferation of a Panel of Eight Glioblastoma Stems Cell Lines: Downregulation of BDR4 as a Novel Anti-Neoplastic Mechanism

In this poster, the authors discuss their preclinical finding that when glioblastoma stem cell lines are treated with VAL-083 there is a downregulation of the transcription activator bromodomain-containing protein 4 (BRD4).

Chromatin remodeling through histone acetylation is a key step in the regulation of the gene expression in both normal and tumor cells. Members of the bromodomain family of proteins, such as BRD4, interact with acetylated histones to assemble chromatin complexes and transcription activators at specific gene promoter sites, including tumor oncogenes. Selective downregulation of bromodomain proteins such as BRD4 by agents such as VAL-083 can therefore inhibit the interaction of BDR4 with acetylated histones at promoter sites, resulting in a reduction of downstream signaling events. Thus, it is possible that VAL-083 may elicit its DNA-damaging action, at least in part, by interrupting chromatin remodeling in cancer cells.

Dianhydrogalactitol (VAL-083) has the Potential to Overcome Major Challenges in the Treatment of Diffuse Intrinsic Pontine Glioma (DIPG)

In this poster, the authors discuss the potential for VAL-083 either as a single-agent, or as part of combination therapy regimens, for the treatment of diffuse intrinsic pontine glioma (DIPG). DIPG is a difficult-to treat, inoperable, rare pediatric brain tumor with very poor prognosis and a dismal survival outlook. In this poster the authors report that VAL-083 is active as a single-agent and synergistic with AZD1775, a Wee1 inhibitor, against DIPG cell lines with varying genetic profile.

Dianhydrogalactitol (VAL-083) Reduces Glioblastoma Tumor Growth In Vivo Upon Bevacizumab-induced Hypoxia

Treatment of GBM with second-line bevacizumab after progression on first-line temozolomide is the standard-of-care for this disease. However, bevacizumab has not only failed to show an improved benefit in these patients, but has also been found to induce intratumor hypoxia, which is then implicated in increased chemoresistance. Preclinically, it has been previously demonstrated that bevacizumab hypoxia upregulates GLUT-1/GLUT-3 glucose transporters. In such a milieu, VAL-083, due to its simple structure, has a unique advantage of enhanced intra-tumoral transport and uptake. The authors seek confirmation of this in-vitro observation in a GBM xenograft model. The data shows that in such mouse models the GBM tumor shrinkage is best when bevacizumab and VAL-083 are administered together compared to when either agent is used as monotherapy.

DelMar’s poster presentations can be viewed on the company’s website at View Source

About VAL-083

VAL-083 (dianhydrogalactitol) is a "first-in-class," bifunctional DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM and ovarian cancer in historical clinical trials sponsored by the U.S. National Cancer Institute (NCI). DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by common mechanisms of chemoresistance, including MGMT, in cancer cell models and animal studies. Further details regarding these studies can be found at:

View Source.

VAL-083 has been granted orphan drug designations by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas. VAL-083 has been granted fast-track status for the treatment of recurrent GBM by the US FDA

On November 20, 2018 Takeda Pharmaceutical Company Limited ("Takeda") reported that it has received clearance from the European Commission (the "EC") for the proposed acquisition of Shire plc ("Shire") announced on May 8, 2018 (the "Acquisition") (Press release, Takeda, NOV 20, 2018, View Source [SID1234531512]).

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 EC’s approval is conditional on Takeda and Shire fulfilling commitments given to the EC in connection with the clearance. Specifically, in relation to the future potential overlap in the area of inflammatory bowel diseases between Takeda’s marketed product Entyvio (vedolizumab) and Shire’s pipeline compound SHP647, Takeda and Shire have committed to divest the pipeline compound SHP647 and certain associated rights. The divestment of SHP647 and certain associated rights is not a condition to the completion of the Acquisition.

SHP647 is an exciting pipeline compound and Takeda expects the asset to attract interest from a number of potential buyers. Takeda remains committed to Entyvio, which has been granted marketing authorization in more than 60 countries and is the cornerstone of Takeda’s diverse specialty gastrointestinal portfolio.

"We are very pleased to have secured clearance from the European Commission, the final regulatory approval required to proceed with our acquisition of Shire," said Christophe Weber, President and Chief Executive Officer of Takeda. "We are another step closer to creating a global, values-based, R&D-driven biopharmaceutical leader, and after several months of constructive dialogue, we are optimistic that our shareholders recognize the significant long-term value creation potential of this powerful combination."

The Acquisition has now received clearances from the European Commission, the United States Federal Trade Commission, the Japan Fair Trade Commission, the State Administration for Market Regulation in China and the Brazilian Administrative Council for Economic Defense, among other regulatory authorities.

As announced on November 12, 2018, Takeda has published a circular containing a notice of its decision to hold an Extraordinary General Meeting of Shareholders (the "EGM") to vote on the necessary matters relating to the proposed Acquisition. The EGM is to be convened at 10:00 a.m. (Tokyo time) on December 5, 2018 at INTEX Osaka, Hall 6B Zone.

Takeda also confirms its previously announced expectation that, subject to receiving the necessary shareholder approvals and sanction of the scheme of arrangement by the Jersey court, completion of the Acquisition will take place on January 8, 2019. Further announcements will be made as appropriate.

About Entyvio (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.1 It is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1).2 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.3 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).4 5 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.

Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active UC and CD, who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist. Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with over 200,000 patient years of exposure to date. 6

Therapeutic Indications

Ulcerative colitis
Vedolizumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.

Crohn’s disease
Vedolizumab is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.

Important Safety Information

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use
Vedolizumab should be administered by a healthcare professional equipped to manage hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering vedolizumab. Observe all patients during infusion and until the infusion is complete.

Infusion-related reactions
In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks.

Infections
Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity. Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier. Vedolizumab treatment is not to be initiated in patients with active, severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment. Before starting treatment with vedolizumab, screening for tuberculosis may be considered according to local practice. Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut-homing lymphocytes, vedolizumab exerts an immunosuppressive effect on the gut. Although no systemic immunosuppressive effect was noted in healthy subjects, the effects on systemic immune system function in patients with inflammatory bowel disease are not known. Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms, and consider neurological referral if they occur. If PML is suspected, treatment with vedolizumab must be withheld; if confirmed, treatment must be permanently discontinued. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months.

Malignancies
The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease. Immunomodulatory medicinal products may increase the risk of malignancy.

Prior and concurrent use of biological products
No vedolizumab clinical trial data are available for patients previously treated with natalizumab. Caution should be exercised when considering the use of vedolizumab in these patients. No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. Therefore, the use of vedolizumab in such patients is not recommended.

Vaccinations
Prior to initiating treatment with vedolizumab all patients should be brought up to date with all recommended immunizations. Patients receiving vedolizumab may receive non-live vaccines (e.g., subunit or inactivated vaccines) and may receive live vaccines only if the benefits outweigh the risks.

Adverse reactions include: nasopharyngitis, headache, arthralgia, upper respiratory tract infection, bronchitis, influenza, sinusitis, cough, oropharyngeal pain, nausea, rash, pruritus, back pain, pain in extremities, pyrexia, and fatigue.

Please consult with your local regulatory agency for approved labeling in your country.

For U.S. audiences, please see the full Prescribing Information including Medication Guide for ENTYVIO.7

For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO.

Takeda’s Commitment to Gastroenterology
Gastrointestinal (GI) diseases can be complex, debilitating and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for over 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies.

On November 19, 2018 Bausch Health Companies Inc. (NYSE/TSX: BHC) reported that the company will participate in three upcoming investor conferences (Press release, Valeant, NOV 19, 2018, View Source [SID1234531479]).

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!

Joseph C. Papa, chairman and chief executive officer, is scheduled to participate at the 30th Annual Piper Jaffray Healthcare Conference in New York on Nov. 27, 2018 at 10:30 a.m. ET.

Paul S. Herendeen, executive vice president and chief financial officer, and Arthur J. Shannon, senior vice president and head of Investor Relations and Communications, are scheduled to participate at the Evercore ISI HealthconX Conference on Nov. 28, 2018 in Boston at 3:30 p.m. ET.

Paul S. Herendeen, executive vice president and chief financial officer, and Arthur J. Shannon, senior vice president and head of Investor Relations and Communications, are scheduled to participate at the 2018 Citi Global Healthcare Conference on Dec. 5, 2018 in New York at 8:45 a.m. ET.

Live webcasts and audio archives of the events will be available on the Investor Relations page of the Bausch Health Companies Inc. web site at: View Source

On November 19, 2018 Bexion Pharmaceuticals, Inc., a clinical – stage biopharmaceutical company focused on rare brain and solid tumors, reported that a clinical oral report followed by poster review and a second case study poster were presented at the Society of Neuro – Oncology (SNO) Annual Meeting held November 16 – 18 in New Orleans, LA (Press release, Bexion, NOV 19, 2018, View Source [SID1234531577]). The SNO Annual Meeting brings together more than 2600 research ers and clinicians in the field of neuro – oncology.

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!

Bexion’s representation:
High – Grade Glioma O utcomes in the Phase 1 BXQ – 350 Trial of Cancer – Selective SapC – DOPS Nanovesicles

Vinay Puduvalli, MD, Professor and Director, Division of Neuro – Oncology, The Ohio State University Comprehensive Cancer Center gave an oral presentation on November 16 th discussing the safety outcomes of High Grade Glioma (HHG) patients from a Phase 1a BXQ – 350 trial (NCT02859857). This was followed by a traditional poster viewing.

Initial Experience in Ependymoma with Investigational Cancer – Targeting BXQ – 350 SapC – DOPS Nanovesicles: A Rare Tumor Case Study

During a poster presentation on Saturday November 17 th , John Villano MD, Director, Clinical Neuro – Oncology Research Program, Markey Cancer Center and Professor of Medicine, University of Kentucky HealthCare discussed the safety profile in a rare tumor type resulting from a Phase 1a BXQ – 350 trial (NCT02859857).

"Bexion was honored to participate in the SNO Annual meeting. We are exc ited to have presented new BXQ – 350 data from our Phase 1 program by our Principal Investigators ," stated Dr. Ray Takigiku, Founder and CEO of Bexion.

About BXQ – 350
BXQ – 350 is a unique formulation of a synthetically produced, human lysosomal protein, Saposin C (sphingolipid activator protein, or SapC), and the phospholipid dioleoylphosphatidylserine (DOPS).

On N ovember 19, 2018 Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE) reported that the Phase III JAVELIN Ovarian 200 trial evaluating avelumab* alone or in combination with pegylated liposomal doxorubicin (PLD), a type of chemotherapy, compared with PLD did not meet the prespecified primary endpoints of overall survival (OS) or progression-free survival (PFS) in patients with platinum-resistant or -refractory ovarian cancer (Press release, Pfizer, NOV 19, 2018, View Source [SID1234531434]). Signals were observed in the combination arm relative to PLD, and further analyses of the trial are warranted (HR for the primary PFS endpoint for avelumab + PLD vs PLD alone: 0.78 [repeated confidence interval (RCI): 0.587, 1.244; one-sided p-value: 0.0301]; HR for the primary OS endpoint for avelumab + PLD vs PLD alone: 0.89 [RCI: 0.744, 1.241; one-sided p-value: 0.2082]; HR for the primary PFS endpoint for avelumab alone vs PLD alone: 1.68 [RCI: 1.320, 2.601; one-sided p-value: >0.99]; HR for the primary OS endpoint for avelumab alone vs PLD alone: 1.14 [RCI: 0.948, 1.580; one-sided p-value: 0.8253]; objective response, a secondary endpoint: 13.3% [95% CI 8.8, 19.0] for avelumab + PLD; 3.7% [95% CI 1.5, 7.5] for avelumab alone; and 4.2% [95% CI 1.8, 8.1] for PLD alone). No new safety signals were observed for avelumab alone or in combination, and the safety profile for avelumab in this trial was consistent with that observed in the overall JAVELIN clinical development program. The data are currently being analyzed, and detailed results will be shared with the scientific community.

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!

"JAVELIN Ovarian 200 enrolled a high proportion of patients with aggressive, refractory disease that had no response to prior platinum-based chemotherapy, a population known to have disease that is challenging to treat; as such, this group of patients is typically not included in Phase III ovarian cancer trials," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "We initiated the JAVELIN Ovarian 200 trial as the first Phase III study of a checkpoint inhibitor in the platinum-resistant or -refractory setting recognizing these patients have the most pressing need for new treatment options. The results speak to the significant challenges these women face."

"Although OS and PFS did not reach statistical significance, study results indicate potential clinical activity of the combination of avelumab and chemotherapy which will be analyzed further," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "We thank the patients, their families and the investigators who participated in the JAVELIN Ovarian 200 trial, and wish to underscore that the alliance remains committed to driving advances in ovarian cancer, a commitment that includes two ongoing Phase III trials in previously untreated patients testing avelumab in combination with chemotherapy and, separately, one in combination with chemotherapy followed by maintenance treatment of avelumab in combination with a PARP inhibitor."

"Effective management of platinum-resistant or -refractory ovarian cancer remains the biggest unmet medical need facing women with recurrent ovarian cancer today. The current treatment options have only limited and short-lived efficacy for the majority of women, as evidenced by an average life expectancy that does not exceed one year for this group," said Eric Pujade-Lauraine, M.D., Ph.D., head of the Women Cancers and Clinical Research Department at Hôpitaux Universitaires Paris Centre, site Hôtel-Dieu. "As a researcher and clinician, I know how important it is to continue to improve the outlook for women with advanced ovarian cancer and look forward to the results of more trials exploring the role of avelumab in delaying recurrence in platinum-sensitive patients and earlier lines of therapy."

Four out of five patients with ovarian cancer are diagnosed at advanced stages. The disease often has no symptoms early on, when it is much more treatable.[1] Approximately 70% of patients with ovarian cancer who receive standard-of-care, frontline, platinum-based chemotherapy will relapse in the first three years.[2] At first relapse, approximately 20% to 25% of ovarian cancer patients have platinum-resistant or -refractory disease, and eventually almost all patients will become platinum-resistant.[3]-[6]

JAVELIN Ovarian 200 is a Phase III, multicenter, randomized study investigating the efficacy and safety of avelumab alone or in combination with PLD versus PLD alone in 566 women with ovarian cancer that is resistant or refractory to platinum chemotherapy. The primary objectives were to demonstrate superior OS or PFS for one or both avelumab-based treatment regimens compared with PLD.

In addition to JAVELIN Ovarian 200, the avelumab ovarian cancer clinical development program includes several ongoing clinical trials investigating avelumab in combination with other therapies. JAVELIN Ovarian 100 is an open-label, international, multicenter, randomized Phase III study of avelumab in combination with and/or as follow-on (maintenance) treatment to platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic (Stage III or Stage IV) epithelial ovarian cancer. JAVELIN Ovarian 100 is the first Phase III study to evaluate the addition of an immunotherapy to the standard of care in frontline treatment for this aggressive disease. JAVELIN Ovarian PARP 100 is a randomized, open-label, multicenter Phase III study of avelumab plus chemotherapy followed by maintenance therapy of avelumab in combination with a PARP inhibitor or chemotherapy followed by maintenance therapy with a PARP inhibitor, in patients with previously untreated advanced ovarian cancer. Avelumab is also undergoing investigation in combination with other therapies for gynecologic cancers.

*Avelumab is under clinical investigation for treatment of ovarian cancer and has not been demonstrated to be safe and effective for this indication. There is no guarantee that avelumab will be approved for ovarian cancer by any health authority worldwide.

About the JAVELIN Clinical Trial Program

The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 9,000 patients evaluated across more than 15 different tumor types. In addition to ovarian cancer, these tumor types include breast, gastric/gastro-esophageal junction and head and neck cancers, melanoma, mesothelioma, Merkel cell carcinoma, non-small cell lung cancer, renal cell carcinoma and urothelial carcinoma.

About Ovarian Cancer

Every year, more than 295,000 women are diagnosed with ovarian cancer worldwide.[7] The disease is generally advanced when it is diagnosed, as it often has few to no symptoms at the early stages. This makes it difficult to detect until the disease has progressed. Symptoms can be vague or non-specific, making it easy to confuse with less serious non-cancerous conditions. The five-year survival rate ranges from approximately 30% to 50%, but for those with metastatic disease, it drops to less than 20%.[7],[8]

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.[9]-[11] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[11]-[13] In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications

In the US, the FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab is currently approved for patients with MCC in more than 35 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

Important Safety Information from the US FDA Approved Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).