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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References:
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causes.
http://www.cancerresearchuk.org/about-cancer/type/all/about/acute-lymphoblastic-leukaemia-risks-and-causes.
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- Mayo Clinic. Acute lymphocytic leukemia.
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Accessed July 20, 2016.
- Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in
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http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-how-classified.
Accessed July 20, 2016.
- Pui CH, et al. Clinical and biologic relevance of immunologic
marker studies in childhood acute lymphoblastic leukemia. Blood.
1993;82(2):343-62.
- 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.
- 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.
- Nguyen K, et al. Factors influencing survival after relapse
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study. Leukemia. 2008;22(12):2142-50.
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