Study Results Published In Journal of Clinical Oncology Show BLINCYTO® (blinatumomab) Induced Complete Remission In Heavily Pretreated Pediatric Patients With Philadelphia Chromosome-Negative Relapsed Or Refractory B-cell Precursor Acute Lymphoblastic Leukemia

THOUSAND OAKS, Calif., Oct. 3, 2016 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that the Journal of Clinical Oncology (JCO) published results from the Phase 1/2 '205 single-arm trial evaluating BLINCYTO^® (blinatumomab) in pediatric patients with Philadelphia chromosome‑negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Based on data from an exploratory pooled analysis of 70 patients who received the recommended dose of BLINCYTO in the Phase 1 or Phase 2 portions of the study, 27 patients (39 percent, 95 percent confidence interval [CI], 27–51 percent) achieved complete remission within the first two cycles.

The most frequent grade ≥3 adverse events (AEs) among the patients who received the recommended dose were anemia (36 percent), thrombocytopenia (21 percent), febrile neutropenia (17 percent), hypokalemia (17 percent) and neutropenia (17 percent). The most common AEs overall were pyrexia (80 percent), anemia (41 percent), nausea (33 percent) and headache (30 percent).

"This study showed that BLINCYTO can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL," said senior author Lia Gore, M.D., professor of Pediatrics, Medical Oncology and Hematology, University of Colorado Anschutz Medical Campus. 

"Pediatric patients with relapsed or refractory Ph- B-cell precursor ALL are in critical need of new treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The publication of this data in the Journal of Clinical Oncology provides clinical evidence of the potential of BLINCYTO in this patient population and underscores the significance of the recent regulatory approval for use of BLINCYTO in these patients."

Among patients who achieved complete remission within the first two cycles of treatment, 52 percent had a complete minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level. Complete MRD response was an exploratory endpoint in both phases of the study.

Data from the '205 study were the basis of a supplemental Biologics License Application (sBLA) for BLINCYTO to include new data supporting the treatment of pediatric patients with Ph- relapsed or refractory B-cell precursor ALL. On Aug. 30, 2016, the U.S. Food and Drug Administration (FDA) approved the sBLA for BLINCYTO to include this new data supporting the treatment of pediatric patients with Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval, and continued approval may be contingent upon verification of clinical benefit in subsequent trials.

ALL is a rapidly progressing cancer of the blood and bone marrow. Although very rare in adults, it is the most common type of cancer in children.^1,2 Of the children diagnosed with  ALL in the U.S. each year, approximately 15-20 percent (375-500) will experience relapse.^3-5 Prognosis for children with ALL who are refractory or experience a relapse is extremely poor, and post-relapse survival is only achieved in 40-50 percent of patients.^6-8

About Study '205
Study '205 evaluated the safety and efficacy of BLINCYTO in a Phase 1/2 open-label, multicenter, single-arm study in 93 pediatric patients with Ph- relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic hematopoietic stem cell transplantation [alloHSCT], or refractory to other treatments and had >25 percent blasts in bone marrow). Treatment in this study has been completed and subjects are being monitored for long-term efficacy.

BLINCYTO was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 5 μg/m²/day on Days 1-7 and 15 μg/m²/day on Days 8-28 for cycle 1, and 15 μg/m²/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO, but later relapsed, had the option to be retreated with BLINCYTO. 

The treated population included 70 patients who received at least one infusion of BLINCYTO at the recommended dose; the median number of treatment cycles was one (range: 1 to 5). Among treated patients, the median age was eight years (range: seven months to 17 years), 40 out of 70 (57.1 percent) had undergone alloHSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7 percent) had refractory disease. Four patients had less than the 25 percent bone marrow blasts required for protocol entry, but had more than five percent. 

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, priority review and orphan drug designations by FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL.

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

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. The median time to onset of elevated liver enzymes was 3 days. In patients receiving BLINCYTO^®, the majority of these events were observed in the setting of CRS. The median time to onset for these events was 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 
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

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No forward-looking statement can be guaranteed and actual results may differ materially from those we project.  Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints we have selected. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market.

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CONTACT:
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Kristen Neese, 805-313-8267 (media)
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References:

1. Cancer Research UK. Acute lymphoblastic leukaemia risks and causes. http://www.cancerresearchuk.org/about-cancer/type/all/about/acute-lymphoblastic-leukaemia-risks-and-causes. Accessed July 20, 2016. 
2. Mayo Clinic. Acute lymphocytic leukemia. http://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915. Accessed July 20, 2016.
3. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2015;373(16):1541-52.
4. American Cancer Society. How is childhood leukemia classified? http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-how-classified. Accessed July 20, 2016.
5. Pui CH, et al. Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia. Blood. 1993;82(2):343-62.
6. Reismuller B, et al. Outcome of Children and Adolescents With a Second or Third Relapse of Acute Lymphoblastic Leukemia (ALL): A Population-based Analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Mu¨nster) Study Group. J Pediatr Hematol Oncol. 2013;35:e200–e204.
7. Hunger SP, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663-9.
8. Nguyen K, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a children's oncology group study. Leukemia. 2008;22(12):2142-50.

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