THOUSAND OAKS, Calif.,
Sept. 24, 2019 /PRNewswire/ -- Amgen
(NASDAQ:AMGN) today announced that the results of a prespecified
interim analysis of an open-label, randomized, controlled global
multicenter Phase 3 trial (20120215) showed that the primary
endpoint of event-free survival was met. The study evaluated the
efficacy, safety and tolerability of BLINCYTO®
(blinatumomab) compared to conventional consolidation chemotherapy
in pediatric patients with high-risk, B-cell acute lymphoblastic
leukemia (ALL) at first relapse. Enrollment was terminated early
due to encouraging efficacy in the BLINCYTO arm and was based on a
recommendation from the Independent Data Monitoring Committee
(DMC). Follow up will continue as prescribed per protocol.
In addition, a randomized, Phase 3 trial (AALL1331) conducted by
the Children's Oncology Group (COG) using BLINCYTO in pediatric
B-cell ALL patients at first relapse has closed to accrual for the
high-risk and intermediate risk-arm based on the recommendation of
the COG DMC. The DMC closure decision was based on a strong trend
towards improved disease-free survival and improved overall
survival, markedly lower toxicity, and better minimal residual
disease (MRD) clearance for BLINCYTO compared to chemotherapy. The
COG DMC recommended that the AALL1331 low-risk group continue to
enroll and randomize patients until enrollment goals are reached.
AALL1331 is sponsored by the Cancer Therapy Evaulation Program of
the National Cancer Institute (NCI), part of the National
Institutes of Health, and is conducted by the NCI-funded COG. Amgen
provided BLINCYTO for AALL1331 under a Collaborative Research and
Development Agreement between the NCI and Amgen.
"Considered together, the results of these studies are
remarkable. Children and adolescents who relapse with acute
lymphoblastic leukemia face a poor prognosis and there remains a
need for additional treatment options, particularly for those that
are identified as high-risk. These data have the potential to be
practice-changing and may provide a treatment approach to prevent
further relapse that is superior to chemotherapy," said
David M. Reese, M.D., executive vice
president of Research and Development at Amgen. "We look forward to
discussing these data with regulatory authorities."
The BLINCYTO adverse events observed in the Phase 3 20120215 and
the COG AALL1331 studies were consistent with the known safety
profile of BLINCYTO. These interim data will be submitted to a
future medical conference and for publication.
About the 20120215 Study
Study 20120215 is a Phase 3 open-label, multicenter, randomized,
controlled trial to evaluate event-free survival after treatment
with BLINCYTO compared with standard of care consolidation
chemotherapy in pediatric patients with high-risk first relapsed
B-cell ALL. Key secondary endpoints included incidence of overall
survival and MRD response, AEs, 100-day mortality after alloHSCT,
incidence of anti-blinatumomab antibody formation, cumulative
incidence of relapse. This is a global study that is being
conducted as part of the PIP (Pediatric Investigation Plan) agreed
to between Amgen and the EMA. The study is being conducted in
Australia and various countries in
EU and Latin America. Click here
to read about the trial on ClinicalTrials.gov.
About the COG AALL1331 Study
The COG AALL1331 study is a risk-stratified, randomized, Phase 3
trial of blinatumomab in first relapse of pediatric B-ALL to
evaluate disease-free survival (DFS) of high-risk (HR) and
intermediate-risk (IR) relapsed B-ALL patients who are randomized
following induction block 1 chemotherapy to receive either two
intensive chemotherapy blocks or two 5-week blocks of blinatumomab.
It also compares the DFS of low risk (LR) relapse B-ALL patients
who are randomized following block 1 chemotherapy to receive either
chemotherapy alone or chemotherapy plus blinatumomab. Key secondary
endpoints include overall survival of HR, IR, and LR relapsed B-ALL
patients. This is a global study that is being conducted in
Australia, Canada, New
Zealand and United States.
Click here to read about the trial on ClinicalTrials.gov.
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.
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.
BLINCYTO was granted breakthrough therapy and priority review
designations by the U.S. Food and Drug Administration and is
approved in the U.S. for the treatment of:
- relapsed or refractory B-cell precursor ALL in adults and
children.
- B-cell precursor ALL in first or second complete remission with
minimal residual disease (MRD) greater than or equal to 0.1% in
adults and children.
This indication is approved under accelerated approval based on MRD
response rate and hematological relapse-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory
trials.
In the EU, BLINCYTO is indicated as monotherapy for the
treatment of:
- adults with Philadelphia
chromosome negative CD19 positive relapsed or refractory
B-precursor acute lymphoblastic leukaemia (ALL).
- adults with Philadelphia
chromosome negative CD19 positive B-precursor ALL in first or
second complete remission with minimal residual disease (MRD)
greater than or equal to 0.1%.
- paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive
B-precursor ALL which is refractory or in relapse after receiving
at least two prior therapies or in relapse after receiving prior
allogeneic hematopoietic stem cell transplantation
About BiTE® Technology
Bispecific T cell engager (BiTE®) technology is a
targeted immuno-oncology platform designed to engage patients' own
T cells to any tumor-specific antigen, activating the cytotoxic
potential of T cells to eliminate detectable cancer. BiTE antibody
constructs are currently being investigated for their potential to
treat a wide variety of cancers. For more information, visit
www.biteantibodies.com.
IMPORTANT SAFETY INFORMATION
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®
and treat with corticosteroids 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 15% of patients with R/R ALL
and in 7% of patients with MRD-positive ALL. The median time to
onset of CRS is 2 days after the start of infusion and the median
time to resolution of CRS was 5 days among cases that resolved.
Closely monitor and advise patients to contact their healthcare
professional 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, and
hemophagocytic histiocytosis/macrophage activation syndrome. If
severe CRS occurs, interrupt BLINCYTO® until CRS
resolves. Discontinue BLINCYTO® permanently if
life-threatening CRS occurs. Administer corticosteroids for severe
or life-threatening CRS.
- 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 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,
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 (91%),
infusion-related reactions (77%), headache (39%), infections
(pathogen unspecified [39%]), tremor (31%), and chills (28%).
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 adults with relapsed or
refractory B-cell precursor ALL 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 increased (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).
Please see full Prescribing Information and medication guide for
BLINCYTO at www.BLINCYTO.com.
About Amgen Oncology
Amgen Oncology is searching for and finding answers to
incredibly complex questions that will advance care and improve
lives for cancer patients and their families. Our research drives
us to understand the disease in the context of the patient's life –
not just their cancer journey – so they can take control of their
lives.
For the last four decades, we have been dedicated to discovering
the firsts that matter in oncology and to finding ways to reduce
the burden of cancer. Building on our heritage, Amgen continues to
advance the largest pipeline in the Company's history, moving with
great speed to advance those innovations for the patients who need
them.
At Amgen, we are driven by our commitment to transform the lives
of cancer patients and keep them at the center of everything we
do.
For more information, follow us on
www.twitter.com/amgenoncology.
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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CONTACT: Amgen, Thousand
Oaks
Trish Hawkins, 805-447-5631
(Media)
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