New formulation can be co-administered with
gastric acid-reducing agents
Tablet offers efficacy, safety and
consistent dosing compared to current capsule
AstraZeneca’s new tablet formulation of CALQUENCE®
(acalabrutinib) has been approved in the US for all current
indications, including adult patients with chronic lymphocytic
leukemia (CLL), small lymphocytic lymphoma (SLL) and for patients
with relapsed or refractory mantle cell lymphoma (MCL), which is
approved under accelerated approval based on overall response
rate.
The approval by the US Food and Drug Administration (FDA) was
based on results from the ELEVATE-PLUS trials presented during the
63rd American Society of Hematology (ASH) Annual Meeting &
Exposition in December 2021.1
In the trials, results showed the CALQUENCE capsule and tablet
formulations are bioequivalent, indicating the same efficacy and
safety profile can be expected with the same dosing strength and
schedule.1 The tablet can be taken with gastric acid-reducing
agents, including proton pump inhibitors (PPIs), antacids and
H2-receptor antagonists (H2RAs).1,2 The majority of observed
adverse events (AEs) in these studies were mild with no new safety
concerns identified.1
John C. Byrd, MD, Chair of the Department of Internal Medicine
at the University of Cincinnati, said: “Patients with blood cancers
like chronic lymphocytic leukemia and mantle cell lymphoma are
often older and may face multiple medical conditions that may need
intervention, including acid reflux or peptic ulcer disease. The US
approval of acalabrutinib in a tablet form enables
co-administration of the acalabrutinib tablet alongside a proton
pump inhibitor. This provides another option for some patients with
chronic lymphocytic leukemia and relapsed or refractory mantle cell
lymphoma, enabling more patients to potentially benefit from this
treatment.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: “Today’s approval of the new CALQUENCE
tablet formulation will offer physicians and patients increased
flexibility when devising treatment plans for chronic lymphocytic
leukemia and mantle cell lymphoma. This new option is a result of
our focus on understanding the wants and needs of this community
and providing patient-focused solutions for their treatment.”
CALQUENCE is also approved as a capsule formulation for the same
indications as the tablet in the US and in many other countries
worldwide.3 Indications may vary by market.
INDICATIONS AND USAGE CALQUENCE is a Bruton tyrosine
kinase (BTK) inhibitor indicated for the treatment of adult
patients with mantle cell lymphoma (MCL) who have received at least
one prior therapy.
This indication is approved under accelerated approval based on
overall response rate. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in confirmatory trials.
CALQUENCE is also indicated for the treatment of adult patients
with chronic lymphocytic leukemia (CLL) or small lymphocytic
lymphoma (SLL).
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib)
tablets Serious and Opportunistic Infections Fatal and
serious infections, including opportunistic infections, have
occurred in patients with hematologic malignancies treated with
CALQUENCE.
Serious or Grade 3 or higher infections (bacterial, viral, or
fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in
clinical trials, most often due to respiratory tract infections
(11% of all patients, including pneumonia in 6%). These infections
predominantly occurred in the absence of Grade 3 or 4 neutropenia,
with neutropenic infection reported in 1.9% of all patients.
Opportunistic infections in recipients of CALQUENCE have included,
but are not limited to, hepatitis B virus reactivation, fungal
pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus
reactivation, cytomegalovirus, and progressive multifocal
leukoencephalopathy (PML). Consider prophylaxis in patients who are
at increased risk for opportunistic infections. Monitor patients
for signs and symptoms of infection and treat promptly.
Hemorrhage Fatal and serious hemorrhagic events have
occurred in patients with hematologic malignancies treated with
CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding
or any central nervous system bleeding) occurred in 3.0% of
patients, with fatal hemorrhage occurring in 0.1% of 1029 patients
exposed to CALQUENCE in clinical trials. Bleeding events of any
grade, excluding bruising and petechiae, occurred in 22% of
patients.
Use of antithrombotic agents concomitantly with CALQUENCE may
further increase the risk of hemorrhage. In clinical trials, major
hemorrhage occurred in 2.7% of patients taking CALQUENCE without
antithrombotic agents and 3.6% of patients taking CALQUENCE with
antithrombotic agents. Consider the risks and benefits of
antithrombotic agents when co-administered with CALQUENCE. Monitor
patients for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3-7 days
pre- and post-surgery depending upon the type of surgery and the
risk of bleeding.
Cytopenias Grade 3 or 4 cytopenias, including neutropenia
(23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%),
developed in patients with hematologic malignancies treated with
CALQUENCE. Grade 4 neutropenia developed in 12% of patients.
Monitor complete blood counts regularly during treatment. Interrupt
treatment, reduce the dose, or discontinue treatment as
warranted.
Second Primary Malignancies Second primary malignancies,
including skin cancers and other solid tumors, occurred in 12% of
1029 patients exposed to CALQUENCE in clinical trials. The most
frequent second primary malignancy was skin cancer, reported in 6%
of patients. Monitor patients for skin cancers and advise
protection from sun exposure.
Atrial Fibrillation and Flutter Grade 3 atrial
fibrillation or flutter occurred in 1.1% of 1029 patients treated
with CALQUENCE, with all grades of atrial fibrillation or flutter
reported in 4.1% of all patients. The risk may be increased in
patients with cardiac risk factors, hypertension, previous
arrhythmias, and acute infection. Monitor for symptoms of
arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and
manage as appropriate.
ADVERSE REACTIONS The most common adverse reactions
(≥20%) of any grade in patients with relapsed or refractory MCL
were anemia,* thrombocytopenia,* headache (39%), neutropenia,*
diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
The most common Grade ≥3 non-hematological adverse reaction
(reported in at least 2% of patients) was diarrhea (3.2%).
*Treatment-emergent decreases (all grades) of hemoglobin (46%),
platelets (44%), and neutrophils (36%) were based on laboratory
measurements and adverse reactions.
Dose reductions or discontinuations due to any adverse reaction
were reported in 1.6% and 6.5% of patients, respectively. Increases
in creatinine to 1.5 to 3 times the upper limit of normal (ULN)
occurred in 4.8% of patients.
The most common adverse reactions (≥30%) of any grade in
patients with CLL were anemia,* neutropenia,* thrombocytopenia,*
headache, upper respiratory tract infection, and diarrhea.
*Treatment-emergent decreases (all grades) of hemoglobin,
platelets, and neutrophils were based on laboratory measurements
and adverse reactions.
In patients with previously untreated CLL exposed to CALQUENCE,
fatal adverse reactions that occurred in the absence of disease
progression and with onset within 30 days of the last study
treatment were reported in 2% for each treatment arm, most often
from infection. Serious adverse reactions were reported in 39% of
patients in the CALQUENCE plus obinutuzumab arm and 32% in the
CALQUENCE monotherapy arm, most often due to events of pneumonia
(7% and 2.8%, respectively).
Adverse reactions led to CALQUENCE dose reduction in 7% and 4%
of patients in the CALQUENCE plus obinutuzumab arm (N=178) and
CALQUENCE monotherapy arm (N=179), respectively. Adverse events led
to discontinuation in 11% and 10% of patients, respectively.
Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and
2.8% of patients in the CALQUENCE combination arm and monotherapy
arm, respectively.
In patients with relapsed/refractory CLL exposed to CALQUENCE,
serious adverse reactions occurred in 29% of patients. Serious
adverse reactions in >5% of patients who received CALQUENCE
included lower respiratory tract infection (6%). Fatal adverse
reactions within 30 days of the last dose of CALQUENCE occurred in
2.6% of patients, including from second primary malignancies and
infection.
Adverse reactions led to CALQUENCE dose reduction in 3.9% of
patients (N=154), dose interruptions in 34% of patients, most often
due to respiratory tract infections followed by neutropenia, and
discontinuation in 10% of patients, most frequently due to second
primary malignancies followed by infection. Increases in creatinine
to 1.5 to 3 times ULN occurred in 1.3% of patients who received
CALQUENCE.
DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid
co-administration of CALQUENCE with a strong CYP3A inhibitor. If
these inhibitors will be used short-term, interrupt CALQUENCE.
After discontinuation of strong CYP3A inhibitor for at least 24
hours, resume previous dosage of CALQUENCE.
Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE
to 100 mg once daily when co-administered with a moderate CYP3A
inhibitor.
Strong CYP3A Inducers: Avoid co-administration of
CALQUENCE with a strong CYP3A inducer. If co-administration is
unavoidable, increase the dosage of CALQUENCE to 200 mg
approximately every 12 hours.
SPECIFIC POPULATIONS Based on findings in animals,
CALQUENCE may cause fetal harm and dystocia when administered to a
pregnant woman. There are no available data in pregnant women to
inform the drug-associated risk. Advise pregnant women of the
potential risk to a fetus.
Pregnancy testing is recommended for females of reproductive
potential prior to initiating CALQUENCE therapy. Advise female
patients of reproductive potential to use effective contraception
during treatment with CALQUENCE and for 1 week following the last
dose of CALQUENCE.
It is not known if CALQUENCE is present in human milk. Advise
lactating women not to breastfeed while taking CALQUENCE and for 2
weeks after the last dose.
Avoid use of CALQUENCE in patients with severe hepatic
impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE
is recommended in patients with mild (Child-Pugh class A) or
moderate (Child-Pugh class B) hepatic impairment.
Please see full Prescribing
Information, including Patient Information.
Notes
CLL CLL is the most prevalent type of leukemia in adults,
with over 100,000 new cases globally in 2019 and an estimated
20,160 new cases in the US in 2022.4,5 Although some people with
CLL may not experience any symptoms at diagnosis, others may
experience symptoms, such as weakness, fatigue, weight loss,
chills, fever, night sweats, swollen lymph nodes and abdominal
pain.6
In CLL, there is an accumulation of abnormal lymphocytes within
the bone marrow. As the number of abnormal cells increases, there
is less room within the marrow for the production of normal white
blood cells, red blood cells and platelets. This could result in
anemia, infection and bleeding.7 B-cell receptor signaling through
BTK is one of the essential growth pathways for CLL.
MCL MCL is an uncommon subtype of B-cell non-Hodgkin
lymphoma.8 MCL comprises about 3-6% of non-Hodgkin lymphomas, with
an annual incidence of 0.5 per 100,000 population in Western
countries; in the US, it is estimated that approximately 4,000 new
cases of MCL are diagnosed each year.8,9 While MCL patients
initially respond to treatment, patients do tend to relapse.8
ELEVATE-PLUS ELEVATE-PLUS is comprised of three Phase I,
open-label, single-dose, cross-over studies conducted in 116
healthy subjects. The trials established bioequivalence between
acalabrutinib tablets (100 mg) and acalabrutinib (100 mg) capsules,
evaluated the PPI effect of acalabrutinib tablets administered in
the presence versus absence of PPI rabeprazole and investigated the
effect of food by comparing acalabrutinib tablets administered with
a high-fat diet versus fasted.1
CALQUENCE CALQUENCE (acalabrutinib) is a next-generation,
selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE
binds covalently to BTK, thereby inhibiting its activity.3,10 In B
cells, BTK signaling results in activation of pathways necessary
for B-cell proliferation, trafficking, chemotaxis and
adhesion.3
CALQUENCE is available for prescribing in capsule and tablet
formulations in the US. CALQUENCE tablets and capsules are approved
in the US for the treatment of CLL and SLL, and for the treatment
of adult patients with MCL who have received at least one prior
therapy.2,3 Capsules have restrictions in relation to use with
gastric acid-reducing agents. The tablets are not licensed in the
European Union.
CALQUENCE capsules are approved for CLL in the EU and many other
countries worldwide and approved in Japan for relapsed or
refractory CLL and SLL. A Phase I trial is currently underway in
Japan for the treatment of front-line CLL.
In the US and several other countries, CALQUENCE capsules are
also approved for the treatment of adult patients with MCL who have
received at least one prior therapy. The US MCL indication is
approved under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials. CALQUENCE is not currently approved for the treatment of
MCL in Europe or Japan.
As part of an extensive clinical development program,
AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in
more than 20 company-sponsored clinical trials. CALQUENCE is being
evaluated for the treatment of multiple B-cell blood cancers,
including CLL, MCL, diffuse large B-cell lymphoma, Waldenstr�m’s
macroglobulinemia, follicular lymphoma and marginal zone
lymphoma.
AstraZeneca in hematology AstraZeneca is pushing the
boundaries of science to redefine care in hematology. We have
expanded our commitment to patients with hematologic conditions,
not only in oncology but also in rare diseases with the acquisition
of Alexion, allowing us to reach more patients with high unmet
needs. By applying our deep understanding of blood cancers,
leveraging our strength in solid tumor oncology and delivering on
Alexion’s pioneering legacy in complement science to provide
innovative medicines for rare diseases, we are pursuing the
end-to-end development of novel therapies designed to target
underlying drivers of disease.
Our goal is to help transform the lives of patients living with
malignant, rare and other related hematologic diseases, shaped by
insights from patients, caregivers and physicians to have the most
meaningful impact.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company’s focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care 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 in
Oncology, Rare Diseases and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, 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.
References
- Sharma S, Pepin X, Burri H, et al. New acalabrutinib
formulation enables co-administration with proton pump inhibitors
and dosing in patients unable to swallow capsules (ELEVATE-PLUS).
[abstract and poster]. Poster presented at: 63rd American Society
of Hematology Annual Meeting and Exposition; December 11-14, 2021;
Atlanta, Georgia. Abs 4365.
- CALQUENCE® (acalabrutinib) tablets [prescribing information].
Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2022.
- CALQUENCE® (acalabrutinib) capsules [prescribing information].
Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
- National Cancer Institute (NCI). Cancer stat facts: leukemia —
chronic lymphocytic leukemia (CLL). NCI website. Accessed August
2022. https://seer.cancer.gov/statfacts/html/clyl.html
- Yao Y, Lin X, Li F, et al. The global burden and attributable
risk factors of chronic lymphocytic leukemia in 204 countries and
territories from 1990 to 2019: analysis based on the global burden
of disease study 2019. Biomed Eng Online. 2022;1:4. doi:
10.1186/s12938-021-00973-6
- American Cancer Society (ACS). Signs and symptoms of chronic
lymphocytic leukemia. ACS website. Accessed August 2022.
https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html
- National Cancer Institute. Chronic lymphocytic leukemia
treatment (PDQ®)–Patient version. NCI website. Accessed August
2022.
https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq
- Cheah CY, Seymour JF and Wang ML. Mantle cell lymphoma. J Clin
Oncol. 2016;34(11):1256-1269. doi: 10.1200/JCO.2015.63.5904
- MD Anderson Cancer Center. What to know about mantle cell
lymphoma. MD Anderson Cancer Center website. Accessed August 2022.
https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html
- Wu J, Zhang M and Liu D. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
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