81% overall response rate and 40% complete
response rate by investigator assessment with consistent results
observed across several pre-specified subgroups of patients
AstraZeneca and Acerta Pharma, its hematology research and
development center of excellence, today presented results from the
open-label, single-arm Phase II ACE-LY-004 clinical trial, which
served as the basis for the recent US Food and Drug Administration
(FDA) accelerated approval of CALQUENCE® (acalabrutinib). The
findings were presented for the first time during an oral session
at the 59th American Society of Hematology (ASH) Annual Meeting
& Exhibition in Atlanta and demonstrate the safety profile and
efficacy of CALQUENCE in the management of previously-treated
mantle cell lymphoma (MCL).
CALQUENCE was granted accelerated approval by the US Food and
Drug Administration (FDA) in October 2017 for the treatment of
adult patients with MCL who have received at least one prior
therapy. This indication is approved based on overall response
rate, and continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said: “These
results presented for the first time to the medical community
highlight the potential of CALQUENCE as a treatment for people with
relapsed or refractory mantle cell lymphoma, a life-threatening
form of blood cancer. These data reinforce the important progress
of our clinical development program as well as our commitment to
advancing the treatment of patients with blood cancers.”
Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma,
The University of Texas MD Anderson Cancer Center, and Principal
Investigator of the ACE-LY-004 MCL clinical trial, said: “Most
people living with mantle cell lymphoma will unfortunately relapse,
and new treatment options are greatly needed. As shown by the
consistent overall response rates observed in this trial across
several pre-specified subgroups, acalabrutinib is a welcome new
treatment option for certain patients with this aggressive blood
cancer.”
Summary of key investigator-assessed efficacy results from
ACE-LY-004, a Phase II open-label, single-arm clinical trial in 124
adult patients with relapsed or refractory MCL (15.2 months median
follow-up):
Efficacy measure
Patients (percent response)
Overall response rate(Complete response +
partial response)
Complete response
Partial response
81% (95% CI: 73,87)
40% (95% CI: 31,49)
41% (95% CI: 32,50)
Stable disease 9% (95% CI: 5,15) Progressive
disease 8% (95% CI: 4,14) Not evaluable
2% (95% CI: 1,7)
Per 2014 Lugano classification response criteria for non-Hodgkin
lymphoma; high concordance was observed between
investigator-assessed and independent review committee assessed
overall response and complete response rates, respectively.
The overall response rate was consistent across multiple
subgroups including age, tumor burden and number or type of prior
treatments. The secondary endpoint of median duration of response
had not yet been reached at 15.2 months median follow-up. The
median time-to-response, an exploratory endpoint, was 1.9 months.
After 12 months of treatment, 72% (95% CI: 62,80) of patients were
still responding to acalabrutinib treatment. The secondary
endpoints of progression-free survival and overall survival had not
yet been reached; at 12 months, the progression-free survival and
overall survival rates were 67% (95% CI: 58,75) and 87% (95% CI:
79,92), respectively.
In this trial, the most common non-hematological adverse
reactions (reported in ≥20% of patients at a median follow-up time
of 15.2 months) were headache (38%), diarrhea (30%), fatigue (26%)
and myalgia (21%), per investigator assessment. Grade 3 or 4
adverse reactions (≥5%) included anemia (12%), neutropenia (11%),
and pneumonia (6%). Please refer to the Important Safety
Information about CALQUENCE (acalabrutinib) below for the adverse
reaction rates as shown in the FDA-approved product label.
A Grade 3 gastrointestinal hemorrhage occurred in 1 patient (1%)
with a history of a gastrointestinal ulcer. Tumor lysis syndrome
was reported in 2 patients (2%). A Grade 5 adverse reaction of
aortic stenosis was reported in 1 patient with previous history and
was not considered related to study treatment.
Treatment discontinuation was primarily due to progressive
disease (31%) or adverse reaction (6%).
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE
(acalabrutinib)
Hemorrhage
Serious hemorrhagic events, including fatal events, have
occurred in the combined safety database of 612 patients with
hematologic malignancies treated with CALQUENCE monotherapy. Grade
3 or higher bleeding events, including gastrointestinal,
intracranial, and epistaxis, have been reported in 2% of patients.
Overall, bleeding events, including bruising and petechiae of any
grade, occurred in approximately 50% of patients with hematological
malignancies.
The mechanism for the bleeding events is not well
understood.
CALQUENCE may further increase the risk of hemorrhage in
patients receiving antiplatelet or anticoagulant therapies, and
patients should be monitored for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3 to 7
days pre- and post-surgery, depending upon the type of surgery and
the risk of bleeding.
Infection
Serious infections (bacterial, viral, or fungal), including
fatal events and opportunistic infections, have occurred in the
combined safety database of 612 patients with hematologic
malignancies treated with CALQUENCE monotherapy. Grade 3 or higher
infections occurred in 18% of these patients. The most frequently
reported Grade 3 or 4 infection was pneumonia. Infections due to
hepatitis B virus (HBV) reactivation and progressive multifocal
leukoencephalopathy (PML) have occurred.
Monitor patients for signs and symptoms of infection and treat
as medically appropriate. Consider prophylaxis in patients who are
at increased risk for opportunistic infections.
Cytopenias
In the combined safety database of 612 patients with hematologic
malignancies, patients treated with CALQUENCE monotherapy
experienced Grade 3 or 4 cytopenias, including neutropenia (23%),
anemia (11%), and thrombocytopenia (8%), based on laboratory
measurements. Monitor complete blood counts monthly during
treatment.
Second Primary Malignancies
Second primary malignancies, including non-skin carcinomas, have
occurred in 11% of patients with hematologic malignancies treated
with CALQUENCE monotherapy in the combined safety database of 612
patients. The most frequent second primary malignancy was skin
cancer, reported in 7% of patients. Advise protection from sun
exposure.
Atrial Fibrillation and Flutter
In the combined safety database of 612 patients with hematologic
malignancies treated with CALQUENCE monotherapy, atrial
fibrillation and atrial flutter of any grade occurred in 3% of
patients, and Grade 3 in 1% of patients. Monitor for atrial
fibrillation and atrial flutter and manage as appropriate.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) of any grade were
anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea
(31%), fatigue (28%), myalgia (21%), and bruising (21%).
*Treatment-emergent decreases (all grades) of hemoglobin (46%),
platelets (44%), and neutrophils (36%) were based on laboratory
measurements and adverse reactions.
The most common Grade ≥ 3 non-hematological adverse reaction
(reported in at least 2% of patients) was diarrhea (3.2%).
Dosage reductions or discontinuations due to any adverse
reaction were reported in 1.6% and 6.5% of patients,
respectively.
Increases in creatinine 1.5 to 3 times the upper limit of normal
occurred in 4.8% of patients.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid co-administration
with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be
used short-term, interrupt CALQUENCE.
Moderate CYP3A Inhibitors: When CALQUENCE is
co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE
dose to 100 mg once daily.
Strong CYP3A Inducers: Avoid co-administration with
a strong CYP3A inducer. If a strong CYP3A inducer cannot be
avoided, increase the CALQUENCE dose to 200 mg twice daily.
Gastric Acid Reducing Agents: If treatment with a
gastric acid reducing agent is required, consider using an
H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before
taking an H2-receptor antagonist. Separate dosing with an antacid
by at least 2 hours.
Avoid co-administration with proton pump inhibitors. Due to the
long-lasting effect of proton pump inhibitors, separation of doses
may not eliminate the interaction with CALQUENCE.
SPECIFIC POPULATIONS
There is insufficient clinical data on CALQUENCE use in pregnant
women to inform a drug-associated risk for major birth defects and
miscarriage. Advise women of the potential risk to a fetus.
It is not known if CALQUENCE is present in human milk. Advise
lactating women not to breastfeed while taking CALQUENCE and for at
least 2 weeks after the final dose.
Please see complete Prescribing
Information including Patient Information.
– ENDS –
NOTES TO EDITORS
About CALQUENCE (acalabrutinib)
CALQUENCE® (acalabrutinib; previously known as ACP-196) is an
inhibitor of Bruton tyrosine kinase (BTK). CALQUENCE binds
covalently to BTK, thereby inhibiting its activity. In B cells, BTK
signaling results in activation of pathways necessary for B cell
proliferation, trafficking, chemotaxis and adhesion.
CALQUENCE was granted accelerated approval by the US Food and
Drug Administration (FDA) in October 2017 for the treatment of
adult patients with mantle cell lymphoma (MCL) who have received at
least one prior therapy. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in confirmatory trials. CALQUENCE is not approved for use outside
of its labeled indication in the US.
The recommended dose of CALQUENCE is one 100mg capsule
taken orally approximately every twelve hours until disease
progression or unacceptable toxicity. CALQUENCE may be
taken with or without food.
CALQUENCE is also in development for the treatment of
multiple B-cell malignancies and other cancers including 1st line
MCL, chronic lymphocytic leukemia (CLL), Waldenstr�m
macroglobulinemia (WM), follicular lymphoma, diffuse large B-cell
lymphoma, and multiple myeloma. It is also being developed as a
monotherapy and in combination trials for solid tumors. More than
35 clinical trials across 40 countries with more than 2,500
patients are underway or have been completed.
CALQUENCE was granted Orphan Drug Designation for the treatment
of patients with CLL, MCL and WM in 2015, and Breakthrough Therapy
Designation in August 2017 by the US FDA for the treatment of
patients with MCL who have received at least one prior therapy.
About Mantle Cell Lymphoma (MCL)
MCL is an aggressive B-cell non-Hodgkin lymphoma (NHL) with poor
prognosis. MCL accounts for approximately 3% of new NHL cases
in the US, with approximately 3,300 new cases of MCL diagnosed each
year. The median age at diagnosis is 68 years, with a 3:1 male
predominance. While MCL patients initially respond to treatment,
there is a high relapse rate.
About the ACE-LY-004 Trial
ACE-LY-004 is a Phase II open-label, single-arm clinical trial
in 124 adult patients with relapsed or refractory MCL. The trial
showed that 81% (95% CI: 73,87) of patients treated with CALQUENCE
achieved an overall response; 40% (95% CI: 31,49) achieved a
complete response and 41% (95% CI: 32,50) achieved a partial
response, per 2014 Lugano classification as assessed by
investigator.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly-growing portfolio of new medicines that have the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines aimed to be launched between 2014 and 2020
and a broad pipeline of small molecules and biologics in
development, we are committed to advance New Oncology as one of
AstraZeneca’s five Growth Platforms focused on lung, ovarian,
breast and blood cancers. In addition to our core capabilities, we
actively pursue innovative partnerships and investments that
accelerate the delivery of our strategy as illustrated by our
investment in Acerta Pharma in hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About Acerta Pharma
Acerta Pharma, a member of the AstraZeneca Group, is creating
novel therapies intended for the treatment of cancer and autoimmune
diseases. AstraZeneca acquired a majority stake interest in Acerta
Pharma, which serves as AstraZeneca’s hematology research and
development center of excellence. For more information, please
visit www.acerta-pharma.com.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular & Metabolic
Diseases and Respiratory. The Company also is selectively active in
the areas of autoimmunity, neuroscience and infection. AstraZeneca
operates in over 100 countries and its innovative medicines are
used by millions of patients worldwide.
For more information, please visit www.astrazeneca-us.com and
follow us on Twitter @AstraZenecaUS.
US-16401 Last Updated 12/17
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