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.

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"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%).

On November 19, 2018 Immunocore Limited, a leading T Cell Receptor (TCR) biotechnology company focused on delivering first-in-class biological therapies that have the potential to transform lives of people with serious diseases, reported it has entered into a new partnership with Genentech, a member of the Roche Group, to expand an existing discovery collaboration (Press release, Immunocore, NOV 19, 2018, View Source [SID1234531435]).

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Genentech and Immunocore will now co-develop Immunocore’s therapeutic candidate IMC-C103C, an ImmTAC molecule targeting tumours that express the protein MAGE-A4 (Melanoma-Associated Antigen A4).

Under the terms of the agreement, Immunocore will lead the first-in-human clinical trial to establish safety and preliminary efficacy of IMC-C103C as both monotherapy and in combination with atezolizumab (Tecentriq). The clinical trial, which is scheduled to commence in early 2019, will enrol patients across a number of solid tumour types. As part of the agreement, Genentech will pay Immunocore $100 million in upfront and near-term milestone payments. Upon establishing proof-of-concept data, Immunocore retains an option to continue to co-develop IMC-C103C through commercialisation, or to fully license the candidate to Genentech in return for royalty and milestone payments.

Andrew Hotchkiss, CEO of Immunocore, said: "MAGE-A4 is a known cancer-associated antigen expressed in a wide range of malignancies. Genentech is a leader in oncology with extensive immunology expertise, with whom we’ve had a good collaborative relationship for several years. We look forward to embarking upon this new partnership to investigate whether IMC-C103C could ultimately improve the lives of people with MAGE-A4 positive cancers."

James Sabry, M.D., Ph.D., Global Head of Pharma Partnering, Roche, commented: "We’ve had a very productive collaboration with Immunocore since we began our initial partnership in 2013. We’re excited to move this first molecule forward, both as a single agent and in combination with Tecentriq, and to further explore the role of T cell receptor-directed medicines in fighting cancer."

On November 16, 2018 Amgen (NASDAQ: AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion to expand the current indication for BLINCYTO (blinatumomab) monotherapy to include adult patients with Philadelphia chromosome negative CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent (Press release, Amgen, NOV 16, 2018, View Source [SID1234531408]). The application included data from the Phase 2 BLAST study in frontline and relapsed/refractory ALL, the largest prospective trial for MRD-positive ALL ever conducted. BLINCYTO, a bispecific CD19-directed CD3 T cell engager, is the first BiTE immunotherapy to receive regulatory approval globally.

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MRD refers to the presence of cancer cells that remain detectable, despite a patient having achieved complete remission by conventional assessment.1 MRD is only measurable through the use of highly sensitive testing methods that detect cancer cells in the bone marrow with a sensitivity of at least one cancer cell in 10,000 cells—versus about one in 20 with a conventional microscope-based evaluation.1-3

"The continued acknowledgment of MRD status as an approvable endpoint is an important step in the larger paradigm shift of ALL management as early intervention within the ALL treatment continuum has been shown to be an important step in eliminating dangerous detectable disease," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We appreciate the efforts undertaken by the ALL community to work with regulators and other decision makers on the role of MRD in recurrence of disease and look forward to a final decision by the European Commission."

The CHMP opinion is based on data from the Phase 2 BLAST study, which found that BLINCYTO induced a complete MRD response, or no detectable MRD, in 78 percent of patients within one treatment cycle. Safety results among MRD-positive patients were consistent with the known safety profile of BLINCYTO in relapsed or refractory B-cell precursor ALL.

The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions based on the decision of the EC. The CHMP previously adopted a negative opinion in July 2018 but revised the opinion following a re-examination request by Amgen.

In March 2018, the U.S. Food and Drug Administration (FDA) approved BLINCYTO for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent. BLINCYTO is the first immunotherapy from Amgen’s BiTE platform, an innovative approach that helps the body’s immune system target cancer cells.

About the BLAST Study
The BLAST study is the largest ever prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, Phase 2 study evaluating the efficacy, safety and tolerability of BLINCYTO in adult patients with MRD-positive B-cell precursor ALL in complete hematologic remission after three or more cycles of intensive chemotherapy. Patients received continuous IV infusion of BLINCYTO 15 μg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo hematopoietic stem cell transplantation at any time after the first cycle, if eligible. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Additional secondary endpoints included incidence and severity of adverse events, overall survival (OS), time to hematological remission and duration of complete MRD response.

Results from the BLAST study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in 2015 and published in Blood in 2018. Long-term OS data results from the BLAST study will also be featured in an oral presentation during the ASH (Free ASH Whitepaper) 2018 Annual Meeting on Dec. 3.

About ALL and MRD
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.4,5 Poor outcomes have been observed in patients who achieve first or second complete hematologic remission but have persistent MRD, which remains detectable at the molecular level after treatment.1,6 Five-year OS rates are as high as 75 percent for patients that achieve MRD-negative status, compared with 33 percent among patients that remain MRD-positive.6 For more information about MRD, please visit AmgenOncology.com.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody construct is an innovative technology that can be engineered to target any tumor antigen expressed by any type of cancer. The protein molecules are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. BiTE antibody construct helps connect the T cells to the targeted cell, with the intent of causing T cells to inject toxins which trigger cancer cell death (apoptosis). Amgen is developing BiTE antibody constructs to uniquely (or specifically) target numerous hematologic malignancies and solid tumors.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the FDA in 2014, and carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved under accelerated approval for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

BLINCYTO is now approved in 57 countries, including all member countries in the European Union and the European Economic Area, Canada, Japan, and Australia.

Important EU BLINCYTO (blinatumomab) Safety Information

This product is subject to additional monitoring in the EU. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO for evidence of CRS, as outlined in the PI.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment, and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms of neurological toxicity and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increase (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

On November 16, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of preliminary clinical data from an ongoing Phase 1/2 trial of its investigational PARP inhibitor, pamiparib, in combination with radiation therapy (RT) and/or temozolomide (TMZ) in patients with newly diagnosed or recurrent/refractory (R/R) glioblastoma multiforme (GBM) (Press release, BeiGene, NOV 16, 2018, View Source;p=irol-newsArticle&ID=2377491 [SID1234531392]). These data are being presented at the 23rd Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO), being held November 15 to 18 in New Orleans, LA. Discovered by BeiGene scientists in Beijing, pamiparib is currently in Phase 3 trials globally and in China as a monotherapy and in Phase 1/2 trials in combination with chemotherapy or immunotherapy for a variety of solid tumors.

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"There are limited treatment options available for patients with newly diagnosed and recurrent/refractory glioblastoma. This trial was designed to evaluate the potential synergies between DNA damaging therapies and/or agents and our investigational PARP inhibitor, pamiparib, which in pre-clinical studies has demonstrated brain penetration and PARP trapping activity. We are excited to continue to assess the potential of pamiparib combinations for a variety of difficult-to-treat cancers where there is urgent global need," commented Amy Peterson, M.D., Chief Medical Officer for Immuno-Oncology at BeiGene.

"While response data are still maturing, these preliminary results demonstrated signs of antitumor activity of pamiparib in combination with radiation therapy in patients with newly diagnosed glioblastoma, as well as in combination with low-dose TMZ in patients with recurrent/refractory glioblastoma including those who previously progressed on TMZ, and support the continued development of these combinations," said Kent Shih, M.D., Senior Investigator of the Neuro-Oncology Program at Sarah Cannon Research Institute.

Summary of Preliminary Results

This open-label, multi-center global Phase 1b/2 multiple-dose and dose-escalation trial of pamiparib plus RT and/or TMZ (NCT03150862) was designed to evaluate the safety, efficacy and clinical activity of the combination in patients with newly diagnosed or R/R GBM. Patients with newly diagnosed GBM with unmethylated MGMT promoter status (Arm A) received pamiparib (60 mg twice a day) over escalating time periods (two, four, or six weeks) in combination with RT over six to seven weeks. Patients with R/R GBM (Arm C) received pamiparib (60 mg twice a day) continuously plus TMZ administered on Days 1 to 21 of each 28-day cycle. After evaluation of safety and tolerability from Arm A and C, Arm B will enroll patients with newly diagnosed GBM and treat them with the triple combination of RT, pamiparib, and TMZ.

As of September 14, 2018, a total of 18 patients with newly diagnosed GBM were enrolled in Arm A (n=3, 6 and 9 in the two-, four-, and six-week cohorts respectively). The median study follow-up duration is 19 weeks (2-54). Five grade >3 adverse events (AE) (chills, diarrhea, fatigue, nausea, vertigo, one [5.6%] each) were considered related to pamiparib or RT. Dose-limiting toxicities of fatigue, vertigo, and chills (one each) were reported.

As of the data cutoff date, 15 of the 18 patients were evaluable for response per modified response assessment in neuro-oncology (mRANO) criteria. Two of 15 patients achieved a partial response (PR, one was confirmed) and six patients achieved stable disease (SD); the disease control rate was 53.3% (95% CI: 26.6-78.7).

In Arm C, eight patients received TMZ at a fixed dose of 40 mg for 21 of 28 days and seven patients received 20 mg TMZ. The median study follow-up duration is 12.9 weeks (0.3-31.4). Grade >3 AEs included anemia (20%), fatigue (13.3%), and decreased lymphocyte (13.3%), which were considered related to pamiparib or TMZ. Dose-limiting toxicities of nausea and neutropenia were reported. The combination of 21 days of 40 mg TMZ with pamiparib was not tolerable; a lower 20 mg TMZ dose evaluation in combination with pamiparib is ongoing.

Ten of the 15 patients were evaluable per mRANO criteria and there were two PRs (one unconfirmed and one confirmed after data cutoff) and three SD.

About Glioblastoma Multiforme
Glioblastoma multiforme, also called glioblastoma, is an aggressive type of cancer where malignant grade IV tumors occur in the brain or spinal cord.2 These are the most common type of malignant brain tumors among adults.3 Symptoms include worsening headaches, nausea, vomiting and seizures. Patients can also present with neurological symptoms which are dependent on the tumor location (for example, weakness or sensory changes of face, arm or leg, balance difficulties and neurocognitive/memory issues).4 Glioblastoma can occur at any age but tends to occur more often in older adults. The five-year relative survival rates for patients with glioblastoma are: 19 percent (age 20-44), eight percent (age 44-54), and five percent (age 55-64).5

About Pamiparib
Pamiparib (BGB-290) is an investigational inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP-DNA complex trapping in preclinical models. Discovered by BeiGene scientists in Beijing, pamiparib is currently in global clinical development as a monotherapy and in combination with other agents for a variety of solid tumor malignancies.

On November 16, 2018 VBL Therapeutics (Nasdaq: VBLT), is reported its results today from its Phase 3 GLOBE study in patients with recurrent glioblastoma (rGBM) which was designed to evaluate VB-111 in combination with bevacizumab (Avastin) (`treatment arm`), compared to bevacizumab (`control arm`) (Press release, VBL Therapeutics, NOV 16, 2018, View Source [SID1234531393]). In March 2018, VBL announced top-line data for the study, which did not demonstrate a benefit in overall survival (OS) or progression-free survival for the treatment arm relative to the bevacizumab control.

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The GLOBE data are being presented today at the 2018 Society for Neuro-Oncology Annual Meeting by Dr. Timothy Cloughesy, MD, Professor of Clinical Neurology and Director of the Neuro-Oncology Program, UCLA School of Medicine and principal investigator of the GLOBE trial. The data include further analyses of the GLOBE data including baseline prognostic factors and subgroups analysis. Data show that the baseline tumor volume, which is a significant prognostic factor in rGBM, was higher in the treatment arm compared to the control arm. Overall, the subjects in the study had relatively high tumor volume, as large-volume tumors were not an exclusion criterion. It is of interest that patients with smaller tumors (<15 cm3) appeared to respond better to the treatment arm, with numerically higher response rate and overall survival observed. Furthermore, a trend towards greater survival was observed in patients treated with VB-111 who reported fever. VB-111 was well tolerated, with a similar early termination rate in both the treatment and control arms. Most frequent adverse event was self-limited fever, starting several hours post therapy and usually resolving by 24 hours. As expected, a higher rate of SAEs and grade >=3 AEs was reported in the combination treatment arm.

Subsequent analyses have focused on the potential reasons for the major differences in outcomes between the positive VB-111 Phase 2 clinical trial in rGBM and the unsuccessful GLOBE results. The Phase 2 trial of VB-111 met the primary endpoint of OS benefit with median OS (mOS) of 13.6 months upon treatment with VB-111 as a single drug (`priming`) followed by adding bevacizumab to VB-111 upon further progression, compared to mOS of 6.8 months for the treatment arm in GLOBE (co-administration of VB-111 and bevacizumab, without any VB-111 monotherapy `priming` period).

Thorough analyses of the baseline risk factors of the Phase 2 and the Phase 3 treatment groups did not reveal any differences. Therefore, patient selection or different patient populations could not explain the difference between the results of the two studies. The only significant change between the Phase 2 and Phase 3 treatment cohorts was in the treatment regimen – the regimen for Phase 2 trial included priming with VB-111 whereas the regimen for GLOBE trial did not.

To test the hypothesis that concomitant treatment with bevacizumab may have a negative effect on VB-111 activity, the Company investigated this combination in a pre-clinical tumor model. The results indicate that treatment with VB-111 in combination with bevacizumab appears to block the anti-tumor the effect of VB-111, compared to VB-111 monotherapy. In addition, a retrospective analysis of a small cohort of 10 patients who were treated concomitantly with VB-111 and bevacizumab for safety evaluation (no priming), was inferior to what was observed with VB-111 priming in the Phase 2 study.

To better understand these results, the Company is collaborating with UCLA scientists in performing thorough analyses of MRI scans for VB-111-primed combination arm patients from the Phase 2 trial, compared to the un-primed combination arm patients in the GLOBE trial.

"Our initial exploratory analyses demonstrate clear radiologic responses over time in rGBM patients treated with VB-111 in the Phase 2 trial, both on VB-111 monotherapy and in combination with bevacizumab after priming with VB-111 alone, which were translated to overall survival. We are currently analyzing the GLOBE MRI scans to see if this signature of VB-111 activity is lost in the GLOBE combination group and will report the outcome upon completion of the analysis," said Dr. Cloughesy.

"The new analyses we have been conducting provide insight into how the VB-111 treatment regimen may influence its anti-tumor effect and help us understand why the positive Phase 2 data were not replicated in the GLOBE Phase 3 study," said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics. "We believe that priming with VB-111 without bevacizumab may be critical for the immune and vascular-disruptive/anti-angiogenic mechanism of VB-111 in rGBM. We continue to have confidence in the ongoing OVAL Phase 3 study of VB-111 in platinum-resistant ovarian cancer patients, whose protocol takes into account lessons learned from our GBM trial. The OVAL Phase 3 study is evaluating VB-111 in combination with chemotherapy rather than Avastin. The combination of VB-111 with paclitaxel worked well both in pre-clinical settings and in our Phase 2 for ovarian cancer, including in patients whose tumors progressed on prior treatment with Avastin. In OVAL, we are repeating exactly the same successful Phase 2 regimen."

For a link to the GLOBE presentation at SNO see: LINK

About the GLOBE study

The GLOBE pivotal Phase 3 trial was a randomized, controlled, double-arm, open-label study of VB-111 dosed every two months in combination with bevacizumab dosed every two weeks, compared to bevacizumab monotherapy. Key inclusion criteria included first or second progression of glioblastoma following standard of care treatment with temozolomide and radiation, a histologically confirmed diagnosis of glioblastoma and measurable disease by RANO criteria at progression.

The study was conducted under a Special Protocol Assessment (SPA) granted by the FDA, with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for promising and meaningful long-term survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation.

About Ofranergene Obadenovec (VB-111)

VB-111, a potential first-in-class anticancer therapeutic candidate, is the Company’s lead oncology product currently being studied in a Phase 3 trial for ovarian cancer. VB-111 has received orphan drug designation in both the US and Europe, and fast track designation in the US for prolongation of survival in patients with rGBM. In addition, VB-111 successfully demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in radioiodine-refractory thyroid cancer and recurrent platinum-resistant ovarian cancer. VB-111 has received an Orphan Designation for the treatment of ovarian cancer by the European Medicines Agency (EMA).