On March 29, 2017 Novartis reported that the US Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) filing and granted priority review for CTL019 (tisagenlecleucel-T), an investigational chimeric antigen receptor T cell (CAR-T) therapy, in relapsed and refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) (Press release, Novartis, MAR 29, 2017, View Source [SID1234518306]). This is the first BLA submission by Novartis for a CAR-T. The priority review designation is expected to shorten the anticipated review time by the FDA.

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CAR-T is different from typical small molecule or biologic therapies currently on the market because it is manufactured for each individual patient. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to hunt the patient’s cancer cells and other B-cells expressing a particular antigen.

"With CTL019, Novartis is at the forefront of the science and development of immunocellular therapy as a potential new innovative approach to treating certain cancers where there are limited options," said Vas Narasimhan, Global Head of Drug Development and Chief Medical Officer, Novartis. "The priority review and file acceptance of CTL019 by the FDA brings us one step closer to delivering this novel treatment option to children and young adults with r/r B-cell ALL in the United States."

CTL019 was first developed by the University of Pennsylvania. In 2012, Novartis and the University of Pennsylvania entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies for the investigational treatment of cancers, including CTL019. Through the collaboration, Novartis holds the worldwide rights to CARs developed through the collaboration with the University of Pennsylvania for all cancer indications.

"The past five years have seen tremendous progress in the development and application of cellular engineering in an effort to personalize the treatment of cancer," said the Penn team’s leader, Carl June, MD, director of the Center for Cellular Immunotherapies in the Perelman School of Medicine at the University of Pennsylvania. "We now know that it is possible to treat patients in clinical trials across the world using this approach, and the results we have observed mark a potential new paradigm in the treatment of blood cancers that have not responded to standard therapies."

The priority review designation and BLA submission for CTL019 is based on the results from the Novartis-sponsored ELIANA study (NCT02435849), the first global CAR-T cell trial with study enrollment having occurred across 25 centers in the US, EU, Canada, Australia and Japan. In the Phase II study, 82% (41 of 50) of patients infused with CAR-T cells achieved complete remission or complete remission with incomplete blood count recovery at three months post CTL019 infusion. The data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in December 2016 (Abstract #221)[1].

Forty-eight percent of patients in the ELIANA trial experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of an investigational therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed per protocol on a global scale using prior site education with implementation of the CRS treatment algorithm. There were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events including confusion, delirium, encephalopathy, agitation and seizure. No cerebral edema was reported and no grade 4 neurological and psychiatric events were observed[1].

The submission is also supported by findings from a US multicenter trial and an earlier single site trial led by the Children’s Hospital of Philadelphia (CHOP) examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL. Stephan Grupp, MD, PhD, from CHOP was the lead investigator of the trials.

"Even if a patient has difficult-to-treat relapsed/refractory leukemia, we have seen treatment with CTL019 in clinical trials put cancer into remission," said Grupp, Director of the Cancer Immunotherapy Frontier Program and Director of Translational Research for the Center for Childhood Cancer Research at CHOP. "This could be a first-of-its-kind treatment with exciting potential to help pediatric and young adult r/r B-cell ALL patients."

Acute lymphoblastic leukemia makes up approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US[2]. Patients with r/r ALL have limited treatment options, and the chance of survival for children with the disease who relapse or fail to attain remission is between 16% to 30%[3].

According to the FDA guidelines, Priority Review status may potentially shorten the window for the agency to take action on an application to within six months of the filing acceptance compared to a standard review. The designation aims to prioritize the evaluation of products that have the potential to provide significant improvements in the treatment, diagnosis or prevention of serious conditions when compared to standard applications. CTL019 previously received Breakthrough Therapy designation from the FDA for the treatment of patients with r/r ALL.

Novartis plans additional filings for CTL019 in the US and EU markets later this year, including a BLA with the FDA for treatment of adults with r/r diffuse large B-cell lymphoma (DLBCL) and applications for marketing authorization with the European Medicines Agency in r/r B-cell ALL and r/r DLBCL.

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "priority review," "commitment," "investigational," "plans," "expected," "potential," "possible," "may," "could," "potentially," "aims to," "designed to," "will," or similar terms, or by express or implied discussions regarding potential additional filings or potential marketing approvals for CTL019, or regarding potential future revenues from CTL019. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that CTL019 will be submitted or approved for sale in any market, or at any particular time. Nor can there be any guarantee that CTL019 will be commercially successful in the future. In particular, management’s expectations regarding CTL019 could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On March 29, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported that an Oncologic Drug Advisory Committee of the U.S. Food and Drug Administration voted 11 to 0 that the benefit/risk of rituximab/hyaluronidase for subcutaneous (under the skin) injection was favorable for patients in the proposed indications of follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia (Press release, Halozyme, MAR 29, 2017, View Source [SID1234518305]). The FDA action date is June 26, 2017.

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"We are pleased with the support from today’s advisory committee," said Dr. Helen Torley, president and chief executive officer. "Upon approval, subcutaneous rituximab would offer a new treatment option for U.S. patients that could reduce the administration time for the rituximab portion of their treatment to 5 to 7 minutes as compared with an hour and a half or more for intravenous administration."

Efficacy, safety, pharmacokinetic and patient-reported outcome data from five clinical studies presented by Genentech, a member of the Roche Group, at today’s advisory committee meeting supported the rituximab SC application.

Rituximab co-formulated with Halozyme’s recombinant human hyaluronidase was approved in Europe in 2014 and is currently marketed as the subcutaneous (SC) formulation of MabThera (rituximab) in approximately 50 countries worldwide.

On March 29, 2017 Amgen (NASDAQ:AMGN) reported that the Journal of Clinical Oncology published results from the Phase 2, open-label ALCANTARA study evaluating the efficacy and safety of BLINCYTO (blinatumomab) in patients with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) who had failed at least one second-generation or later tyrosine kinase inhibitor (TKI) (Press release, Amgen, MAR 29, 2017, View Source [SID1234518304]). The study, one of the largest conducted in this patient population (n=45), found that 16 patients (36 percent, 95 percent CI, 22−51 percent) achieved complete remission or complete remission with partial hematologic recovery within the first two cycles of treatment, with 14 of the 16 (31 percent, 96 percent CI, 18–47 percent) patients achieving complete remission with full hematologic recovery.

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BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct. It is the first bispecific immunotherapy from Amgen’s BiTE platform, which helps the body’s immune system target cancer cells and represents an entirely new area of oncology research. BiTE immunotherapy is currently being investigated for its potential to treat a wide variety of cancers.

"Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs," said Anthony Stein, M.D., study investigator and co-director of the Gehr Family Center for Leukemia Research, City of Hope, Duarte, Calif. "Results from this Phase 2 study showed blinatumomab induced complete remission in these high-risk patients regardless of prior TKI therapy or mutational status, reinforcing the potential of BiTE immunotherapy as a targeted therapy option for this difficult-to-treat patient population."

Among patients who achieved complete remission or complete remission with partial hematologic recovery within the first two cycles of treatment, 88 percent had a complete minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level. Response was consistent regardless of ABL1 kinase domain mutational status with 40 percent of patients with a T315I mutation, including those who had received prior ponatinib, demonstrating a complete remission or complete remission with partial hematologic recovery. All of these responders also achieved a complete MRD response.

Additionally, results showed that median relapse-free survival (RFS) was 6.7 months (95 percent CI, 4.4 to not estimable [NE] months), with a median follow up of 9.0 months. Median overall survival (OS) was 7.1 months (95 percent CI, 5.6 to NE months) with or without censoring for allogeneic hematopoietic stem cell transplantation (alloHSCT), with a median follow up of 8.8 months.

"The presence of mutations in patients with Ph+ ALL often leads to relapse and is frequently associated with drug resistance, underscoring the need for new, more effective treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The data published today in the Journal of Clinical Oncology found that BLINCYTO demonstrated antileukemic activity in this heavily pretreated patient population, and we look forward to working with regulatory authorities to make BLINCYTO available to patients with this rare and difficult-to-treat type of ALL."

The most frequent adverse events were pyrexia (58 percent), febrile neutropenia (40 percent) and headache (31 percent). No incidences of grade 3 or higher cytokine release syndrome were reported. Three patients had grade 3 neurologic events. There were no grade 4 or 5 neurologic events.

About the ALCANTARA Study
The ALCANTARA study was a Phase 2, single-arm, multicenter, open-label study investigating the efficacy and tolerability of BLINCYTO in 45 adult patients with Ph+ B-cell precursor ALL, who had relapsed after or were refractory to at least one second-generation or later TKI, or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. BLINCYTO was administered in 28-day cycles by continuous intravenous infusion. The primary endpoint was complete remission or complete remission with partial hematologic recovery during the first two cycles. Key secondary endpoints included MRD response, rate of alloHSCT, RFS, OS and adverse events.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration (FDA), and is now approved in the U.S. for the treatment of Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

In November 2015, BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

BLINCYTO U.S. Product Safety 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. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).
Neurological Toxicities: Approximately 64% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 17% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The neurological toxicity profile varied by age group. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO experienced serious 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): 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 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 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% 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.
Adverse Reactions

The most common adverse reactions (≥ 20%) in the safety population studied in clinical trials were pyrexia (66%), headache (34%), nausea (27%), edema (26%), hypokalemia (26%), anemia (25%), febrile neutropenia (24%), neutropenia (22%), thrombocytopenia (20%), and abdominal pain (20%). The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. For some adverse reactions, there were differences in the incidence rates by age subgroup.
In patients weighing greater than or equal to 45 kg, serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia (9%), pyrexia (6%), sepsis (5%), pneumonia (5%), device-related infection (4%), neutropenia (3%), tremor (3%), overdose (3%), encephalopathy (3%), infection (2%), confusion (3%) and headache (2%).
In patients weighing less than 45 kg, serious adverse reactions were reported in 51% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia (12%), febrile neutropenia (9%), cytokine release syndrome (4%), convulsion (4%), device-related infection (4%), hypoxia (4%), sepsis (4%), and overdose (4%).
U.S. 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).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO at www.BLINCYTO.com.

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

On March 29, 2017 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) has accepted for priority review the supplemental Biologics License Application (sBLA) for BLINCYTO (blinatumomab) to include overall survival (OS) data from the Phase 3 TOWER study (Press release, Amgen, MAR 29, 2017, View Source [SID1234518303]). The application also includes new data supporting the treatment of patients with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The application aims to expand BLINCYTO’s indication for the treatment of all patients with relapsed or refractory B-cell precursor ALL and supports the conversion of BLINCYTO’s accelerated approval to full approval.

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"Patients with relapsed or refractory ALL generally have a very poor prognosis. The median overall survival – or OS – on standard of care chemotherapy is just four months," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "BLINCYTO is the first-and-only approved bispecific immunotherapy with superior OS results versus standard of care chemotherapy, nearly doubling the median OS for patients with this form of ALL. We look forward to making this important potential new option available to patients with all forms of relapsed or refractory B-cell ALL."

Priority review is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions. The Prescription Drug User Fee Act (PDUFA) target action date is Aug. 14, 2017.

BLINCYTO, the first-and-only FDA-approved CD19-directed CD3 bispecific T cell engager (BiTE) antibody, was previously granted breakthrough therapy designation and accelerated approval. It is also the first single-agent immunotherapy approved to treat patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL.

The application is based on results from the TOWER study, investigating the efficacy of BLINCYTO versus standard of care (SOC) chemotherapy in adult patients with Ph- relapsed or refractory B-cell precursor ALL, which found that BLINCYTO demonstrated a statistically significant improvement in OS over SOC chemotherapy, almost doubling median OS. The study showed that median OS was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus four months (95 percent CI: 2.9, 5.3) for SOC (hazard ratio for death=0.71; p=0.012). BLINCYTO more than doubled median OS versus chemotherapy when used early (in first salvage; 11.1 months versus 5.3 months). Per the recommendation of an independent data monitoring committee, Amgen ended the study early for efficacy. These results were presented during the Presidential Symposium at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) and published in the New England Journal of Medicine.

Safety results among patients who received BLINCYTO were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL. For the most common adverse events (greater than or equal to 10 percent incidence rate) in the BLINCYTO arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least five percent higher for BLINCYTO compared to SOC chemotherapy.

The application also includes data from the ALCANTARA study, evaluating the efficacy and tolerability of BLINCYTO in adult patients with Ph+ relapsed or refractory B-cell precursor ALL, which were published today in the Journal of Clinical Oncology.

The FDA-approved prescribing information for BLINCYTO includes a boxed warning for cytokine release syndrome and neurologic toxicities. BLINCYTO is also under a REMS program in the US.

ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.3 In adult ALL, approximately 75 percent is B-cell precursor ALL, of which 75-80 percent is Ph-, and roughly half will be refractory to treatment or experience relapse.4

About the TOWER Study
The TOWER study was a Phase 3, randomized, active-controlled, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. The study enrolled a difficult-to-treat patient population which included patients from several stages of relapse, 17 percent of whom had relapsed post-allogenic stem cell transplant (alloSCT), and excluded those with late first relapse (≥ 12 months after initial remission). Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of one of four protocol-defined SOC chemotherapy regimens (n=134). The primary endpoint was OS. Key secondary endpoints included complete remission within 12 weeks, the combined endpoint of complete remission plus complete remission with partial or incomplete hematologic recovery and event-free survival. Other secondary endpoints included remission duration, minimal residual disease (MRD) remission (<10–4), alloSCT rate and adverse event rates.

The TOWER study is the confirmatory trial for BLINCYTO. Click here to read about the trial on ClinicalTrials.gov.

About the ALCANTARA Study
The ALCANTARA study was a Phase 2, single-arm, multicenter, open-label study investigating the efficacy and tolerability of BLINCYTO in 45 adult patients with Ph+ B-cell precursor ALL, who had relapsed after or were refractory to at least one second-generation or later tyrosine kinase inhibitor (TKI), or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. BLINCYTO was administered in 28-day cycles by continuous intravenous infusion. The primary endpoint was complete remission or complete remission with partial hematologic recovery during the first two cycles. Key secondary endpoints included MRD response, rate of alloHSCT, relapsed free survival, OS and adverse events.

Safety results among subjects who received BLINCYTO were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy and priority review designations by the FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

In November 2015, BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

BLINCYTO U.S. Product Safety 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. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).
Neurological Toxicities: Approximately 64% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 17% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The neurological toxicity profile varied by age group. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO experienced serious 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): 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 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 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% 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.
Adverse Reactions

The most common adverse reactions (≥ 20%) in the safety population studied in clinical trials were pyrexia (66%), headache (34%), nausea (27%), edema (26%), hypokalemia (26%), anemia (25%), febrile neutropenia (24%), neutropenia (22%), thrombocytopenia (20%), and abdominal pain (20%). The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. For some adverse reactions, there were differences in the incidence rates by age subgroup.
In patients weighing greater than or equal to 45 kg, serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia (9%), pyrexia (6%), sepsis (5%), pneumonia (5%), device-related infection (4%), neutropenia (3%), tremor (3%), overdose (3%), encephalopathy (3%), infection (2%), confusion (3%) and headache (2%).
In patients weighing less than 45 kg, serious adverse reactions were reported in 51% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia (12%), febrile neutropenia (9%), cytokine release syndrome (4%), convulsion (4%), device-related infection (4%), hypoxia (4%), sepsis (4%), and overdose (4%).
U.S. 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).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO at www.BLINCYTO.com.