Data from two Phase I/II trials presented at
American Society of Hematology Annual Meeting on efficacy and
safety profile of acalabrutinib as monotherapy and combination
treatment
Findings highlight overall response rates and
emerging safety profile of acalabrutinib, a Bruton tyrosine kinase
(BTK) inhibitor
AstraZeneca and Acerta Pharma, its hematology research and
development center of excellence, today presented results from the
Phase Ib/II ACE-CL-003 clinical trial (Abstract #432) and updated
results from the Phase I/II ACE-CL-001 (Abstract #498) clinical
trial that are evaluating acalabrutinib alone and in combination
for the treatment of chronic lymphocytic leukemia (CLL) in multiple
treatment settings. The findings were presented during two oral
sessions at the 59th American Society of Hematology (ASH) Annual
Meeting & Exhibition in Atlanta.
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said: “These
data add to the growing body of evidence that supports the
potential of acalabrutinib in the treatment of chronic lymphocytic
leukemia, a life-threatening disease that affects tens of thousands
of people around the world. These emerging clinical data underscore
AstraZeneca’s commitment to advancing the science of blood cancer
treatments.”
Jennifer Woyach, MD, Associate Professor of Internal Medicine,
Division of Hematology, The Ohio State University Comprehensive
Cancer Center – Arthur G. James Cancer Hospital and Richard J.
Solove Research Institute, said: “Despite treatment advances for
chronic lymphocytic leukemia in recent years, the urgent need for
additional treatment options remains. The overall response rates
observed in the acalabrutinib trials and presented at ASH highlight
the potential impact that this investigational treatment could have
on the management of CLL.”
New, early acalabrutinib data from ACE-CL-003
combination therapy trial
Data on two patient cohorts treated with acalabrutinib and
obinutuzumab from the Phase Ib/II ACE-CL-003 trial were presented.
The primary endpoint of overall response rate was 95% (95% CI:
74,100) for the 19 patients in the treatment-naïve cohort and 92%
(95% CI: 75,99) in the 26 patients with relapsed or refractory CLL.
Additionally, the complete response rate was 16% for
treatment-naïve patients and 8% for previously-treated patients. At
approximately 2 years median study follow-up, the secondary
endpoints of duration of response and median progression-free
survival had not yet been reached in either patient cohort.
Across both cohorts in the trial, the most common adverse
reactions (≥25%) of any grade were upper respiratory tract
infection (69%), maculopapular rash (64%), increased weight (64%),
diarrhea (62%), cough (58%), nausea (51%), headache (47%),
infusion-related reaction (42%), contusion (42%), dizziness (42%),
arthralgia (40%), vomiting (40%), constipation (38%), hypertension
(38%), skin lesion (38%), fatigue (36%), peripheral edema (36%),
decreased appetite (33%), sinusitis (33%), fall (31%), myalgia
(31%), oral pain (31%), dyspepsia (27%) and paraesthesia (27%). One
patient with relapsed or refractory CLL who had a history of atrial
fibrillation experienced intermittent atrial fibrillation (Grade
3), which was not considered treatment related and did not lead to
treatment discontinuation.
Updated acalabrutinib monotherapy safety and efficacy data
from ACE-CL-001 trial
In a separate oral session, investigators presented new
longer-term follow-up safety (primary endpoint) and efficacy
(secondary endpoint) data evaluating acalabrutinib as a monotherapy
in the full-study cohort of 134 patients with relapsed or
refractory CLL at median time on study and follow-up of 24.5
months. These data expand on previously reported findings in 61
patients at median follow-up of 14.3 months.
These latest findings from the trial highlight the overall
response rate and duration of response in this patient population.
With a median follow-up of 24.5 months, the overall response rate
was 87% (95% CI: 80,92) and the overall response including partial
response with lymphocytosis (increase in number of lymphocytes in
the blood) was 93% (95% CI: 88,97). The complete response was 4% (3
patients). The median progression-free survival, a secondary
endpoint in the trial, was not yet reached; however, the 18-month
progression-free survival rate was 90% (95% CI: 83,94).
In this trial, the most common adverse reactions (≥20%) of any
grade were diarrhea (48%), headache (47%), upper respiratory tract
infection (31%), fatigue (28%), nausea (26%), cough (24%),
arthralgia (25%), pyrexia (23%), contusion (23%), weight increased
(21%), petechiae (21%) and constipation (20%). Grade ≥3 adverse
reactions (≥5% of patients) were neutropenia (12%) and pneumonia
(11%). 22% of patients discontinued treatment.
The Phase I/II CLL clinical trial (ACE-CL-003 and ACE-CL-001)
findings are part of an extensive development program for
acalabrutinib in a range of blood cancers, which includes three
ongoing Phase III clinical trials (ACE-CL-006, ACE-CL-007 and
ACE-CL-309) in patients with CLL.
INDICATION AND IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE
(acalabrutinib)
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.
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.
NOTES TO EDITORS
About CALQUENCE (acalabrutinib)
CALQUENCE® (acalabrutinib, previously known as ACP-196 is an
inhibitor of Bruton tyrosine kinase (BTK). Acalabrutinib 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 labelled indication in the US.
Acalabrutinib is in development for the treatment of multiple
B-cell malignancies and other cancers including CLL, MCL,
Waldenstr�m macroglobulinemia (WM), follicular lymphoma, diffuse
large B-cell lymphoma, and multiple myeloma. It is also being
studied as a monotherapy and in combination trials for the
treatment of solid tumors. More than 35 clinical trials across 40
countries with more than 2,500 patients are underway or have
completed.
Acalabrutinib was granted Orphan Drug Designation by the US FDA
in 2015 for the treatment of patients with CLL, MCL and WM.
About Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most common type of
leukemia in adults and accounts for approximately one in four cases
of leukemia. The average age at the time of diagnosis is
approximately 71 years of age. In CLL, too many blood stem cells in
the bone marrow become abnormal lymphocytes and these abnormal
cells have difficulty fighting infections. As the number of
abnormal cells grows there is less room for healthy white blood
cells, red blood cells and platelets. This could result in anemia,
infection and uncontrolled bleeding. B cell receptor signaling
through BTK is one of the essential growth pathways for CLL.
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 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 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 main 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-16400 Last Updated 12/17
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