NORTH CHICAGO, Ill.,
Nov. 8, 2019 /PRNewswire/
-- AbbVie (NYSE: ABBV), a research-based global
biopharmaceutical company, today announced it has submitted a
supplemental New Drug Application (sNDA) to the U.S. Food and Drug
Administration (FDA) for IMBRUVICA® (ibrutinib) in
combination with rituximab for the first-line treatment of younger
patients (70 years old or younger) with chronic lymphocytic
leukemia (CLL) or small lymphocytic lymphoma (SLL). The submission
is based on results from the Phase 3 E1912 study – designed and
conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and
sponsored by the National Cancer Institute (NCI), part of the
National Institutes of Health. The study showed significantly
improved progression-free survival (PFS) and overall survival (OS)
in patients treated with IMBRUVICA plus rituximab, compared to
those treated with fludarabine, cyclophosphamide and rituximab
(FCR). Safety data were consistent with the known safety profile of
IMBRUVICA.
"While therapeutic approaches in chronic lymphocytic leukemia
have improved dramatically over the past several years,
chemoimmunotherapy, which can often be an aggressive course for
even those who are fit enough to tolerate it, has remained a
standard of care for many previously untreated patients," said
Danelle James, M.D., M.A.S.,
IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie
company. "We are pleased that the FDA recognizes the urgent need to
bring a more efficacious treatment option to younger adult patients
with CLL who are considered candidates for chemoimmunotherapy. We
look forward to working closely with the agency during the review
of the landmark Phase 3 E1912 clinical trial data to bring the
IMBRUVICA combination regimen to younger adult patients as quickly
as possible."
The application is being reviewed under the Real-Time Oncology
Review (RTOR) pilot program, which allows the FDA to review data
before the applicant formally submits the complete application. The
program is designed to explore a more efficient review process to
ensure safe and effective treatments become available to patients
earlier, while maintaining quality of review.
IMBRUVICA is a once-daily, first-in-class Bruton's tyrosine
kinase (BTK) inhibitor that is administered orally, and is jointly
developed and commercialized by Pharmacyclics LLC, an AbbVie
company, and Janssen Biotech, Inc.
About the E1912 Study1
Results from the Phase 3 E1912 study were presented during a
Late-Breaking Abstract session at the 2018 American Society of
Hematology (ASH) Annual Meeting and recently published in The
New England Journal of Medicine. The study evaluated 529
previously untreated CLL patients aged 70 or younger, who were
randomly assigned to receive IMBRUVICA plus rituximab (n=354) or
the chemoimmunotherapy FCR (n=175). The primary endpoint was PFS
with a secondary endpoint of OS. The study was led by ECOG-ACRIN
with study site participation by groups in the NCI's National
Clinical Trials Network (Alliance for Clinical Trials in Oncology,
ECOG-ACRIN, NRG Oncology and SWOG), and was sponsored by the NCI.
Pharmacyclics LLC supported the study through a Cooperative
Research and Development Agreement with the NCI.
About IMBRUVICA
IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works
differently than chemotherapy as it blocks a protein called
Bruton's tyrosine kinase (BTK). The BTK protein sends important
signals that tell B cells to mature and produce antibodies. BTK
signaling is needed by specific cancer cells to multiple and
spread.2,3 By blocking BTK, IMBRUVICA may help move
abnormal B cells out of their nourishing environments in the lymph
nodes, bone marrow, and other organs.4
Since its launch in 2013, IMBRUVICA has received 10 FDA
approvals across six disease areas: chronic lymphocytic leukemia
(CLL) with or without 17p deletion (del17p); small lymphocytic
lymphoma (SLL) with or without del17p; Waldenström's
macroglobulinemia (WM); previously-treated patients with mantle
cell lymphoma (MCL)*; previously-treated patients with marginal
zone lymphoma (MZL) who require systemic therapy and have received
at least one prior anti-CD20-based therapy* – and
previously-treated patients with chronic graft-versus-host disease
(cGVHD) after failure of one or more lines of systemic
therapy.5
IMBRUVICA is now approved in 95 countries and has been used to
treat more than 170,000 patients worldwide across its approved
indications. IMBRUVICA is the only FDA-approved medicine in WM and
cGVHD. IMBRUVICA has been granted four Breakthrough Therapy
Designations from the U.S. FDA. This designation is intended to
expedite the development and review of a potential new drug for
serious or life-threatening diseases. IMBRUVICA was one of the
first medicines to receive FDA approval via the Breakthrough
Therapy Designation pathway.
The NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) for CLL recommends ibrutinib
(IMBRUVICA®) as a preferred regimen for the initial
treatment of CLL/SLL and it is the only Category 1 single-agent
regimen for treatment-naïve patients without deletion 17p.
IMBRUVICA is being studied alone and in combination with other
treatments in several blood and solid tumor cancers and other
serious illnesses. IMBRUVICA is the most comprehensively studied
BTK inhibitor, with more than 150 ongoing clinical trials. There
are approximately 30 ongoing company-sponsored trials, 14 of which
are in Phase 3, and more than 100 investigator-sponsored trials and
external collaborations that are active around the world. For more
information, visit www.IMBRUVICA.com.
*Accelerated approval was granted for the MCL and MZL
indications based on overall response rate. Continued approval for
MCL and MZL may be contingent upon verification and description of
clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in
patients treated with IMBRUVICA®. Major hemorrhage
(≥ Grade 3, serious, or any central nervous system events;
e.g., intracranial hemorrhage [including subdural hematoma],
gastrointestinal bleeding, hematuria, and post procedural
hemorrhage) have occurred in 4% of patients, with fatalities
occurring in 0.4% of 2,838 patients exposed to
IMBRUVICA® in 27 clinical trials. Bleeding events
of any grade, including bruising and petechiae, occurred in 39% of
patients treated with IMBRUVICA®.
The mechanism for the bleeding events is not well
understood.
Use of either anticoagulant or antiplatelet agents concomitantly
with IMBRUVICA® increases the risk of major hemorrhage.
In IMBRUVICA® clinical trials, 3.1% of patients taking
IMBRUVICA® without antiplatelet or anticoagulant therapy
experienced major hemorrhage. The addition of antiplatelet
therapy with or without anticoagulant therapy increased this
percentage to 4.4%, and the addition of anticoagulant therapy with
or without antiplatelet therapy increased this percentage to
6.1%. Consider the risks and benefits of anticoagulant or
antiplatelet therapy when co-administered with IMBRUVICA®. Monitor
for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA®
for at least 3 to 7 days pre- and post-surgery depending upon the
type of surgery and the risk of bleeding.
Infections: Fatal and non-fatal infections (including
bacterial, viral, or fungal) have occurred with
IMBRUVICA® therapy. Grade 3 or greater infections
occurred in 24% of 1,124 patients exposed to IMBRUVICA®
in clinical trials. Cases of progressive multifocal
leukoencephalopathy (PML) and Pneumocystis jirovecii
pneumonia (PJP) have occurred in patients treated with
IMBRUVICA®. Consider prophylaxis according to standard
of care in patients who are at increased risk for opportunistic
infections.
Monitor and evaluate patients for fever and infections and treat
appropriately.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias
including neutropenia (23%), thrombocytopenia (8%), and anemia (3%)
based on laboratory measurements occurred in patients with B‑cell
malignancies treated with single agent IMBRUVICA®.
Monitor complete blood counts monthly.
Cardiac Arrhythmias: Fatal and serious cardiac
arrhythmias have occurred with IMBRUVICA® therapy.
Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of
patients, and Grade 3 or greater atrial fibrillation and atrial
flutter occurred in 4% of 1,124 patients exposed to
IMBRUVICA® in clinical trials. These events have
occurred particularly in patients with cardiac risk factors,
hypertension, acute infections, and a previous history of cardiac
arrhythmias.
Periodically monitor patients clinically for cardiac
arrhythmias. Obtain an ECG for patients who develop arrhythmic
symptoms (e.g., palpitations, lightheadedness, syncope, chest pain)
or new onset dyspnea. Manage cardiac arrhythmias
appropriately, and if it persists, consider the risks and benefits
of IMBRUVICA® treatment and follow dose modification
guidelines.
Hypertension: Hypertension of any grade occurred in 12%
of 1,124 patients treated with IMBRUVICA® in clinical
trials. Grade 3 or greater hypertension occurred in 5% of patients
with a median time to onset of 5.9 months (range, 0.03 to 24
months).
Monitor blood pressure in patients treated with
IMBRUVICA® and initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA® as
appropriate.
Second Primary Malignancies: Other malignancies (10%)
including non-skin carcinomas (4%) have occurred in 1,124 patients
treated with IMBRUVICA® in clinical trials. The most
frequent second primary malignancy was non-melanoma skin cancer
(6%).
Tumor Lysis Syndrome: Tumor lysis syndrome has been
infrequently reported with IMBRUVICA® therapy. Assess
the baseline risk (e.g., high tumor burden) and take appropriate
precautions.
Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity: Based on findings in animals,
IMBRUVICA® can cause fetal harm when administered to a
pregnant woman. Advise women to avoid becoming pregnant while
taking IMBRUVICA® and for 1 month after cessation of
therapy. If this drug is used during pregnancy or if the patient
becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to a fetus. Advise men to avoid
fathering a child during the same time period.
ADVERSE REACTIONS
B-cell malignancies: The most common adverse
reactions (≥20%) in patients with B-cell malignancies (MCL,
CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%),
anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash
(32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage
(24%), and pyrexia (20%).
The most common Grade 3 or 4 adverse reactions (≥5%) in patients
with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were
neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia
(14%).
Approximately 7% (CLL/SLL),
14% (MCL), 14% (WM)
and 10% (MZL) of patients had a
dose reduction due to adverse reactions.
Approximately 4-10% (CLL/SLL), 9% (MCL), and
7% (WM [5%] and MZL [13%]) of patients
discontinued due to adverse reactions.
cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%),
stomatitis (29%), nausea (26%),
hemorrhage (26%), anemia (24%)*, and pneumonia
(21%).
The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were
pneumonia (14%), fatigue (12%), diarrhea (10%),
neutropenia (10%)*, sepsis (10%), hypokalemia (7%),
headache (5%), musculoskeletal pain (5%), and pyrexia
(5%).
Twenty-four percent of patients receiving IMBRUVICA®
in the cGVHD trial discontinued treatment due to adverse reactions.
Adverse reactions leading to dose reduction occurred in 26% of
patients.
*Treatment-emergent decreases (all grades) were based on
laboratory measurements.
DRUG INTERACTIONS
CYP3A Inhibitors: Co-administration of
IMBRUVICA® with strong or moderate CYP3A inhibitors may
increase ibrutinib plasma concentrations. Dose modifications of
IMBRUVICA® may be recommended when used concomitantly
with posaconazole, voriconazole, and moderate CYP3A inhibitors.
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt
IMBRUVICA® if strong inhibitors are used short-term
(e.g., for ≤ 7 days). See dose modification guidelines in USPI
sections 2.4 and 7.1.
CYP3A Inducers: Avoid coadministration with strong CYP3A
inducers.
SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid
use of IMBRUVICA® in patients with severe baseline
hepatic impairment. In patients with mild or moderate impairment,
reduce IMBRUVICA® dose.
Please click here
for full Prescribing Information.
IMBRUVICA is a registered trademark of Pharmacyclics LLC.
1 Shanafelt, T., et al. Ibrutinib–Rituximab or
Chemoimmunotherapy for Chronic Lymphocytic Leukemia. The New
England Journal of Medicine. August
1,
2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1817073. Accessed
October 2019.
2 Genetics Home Reference. Isolated growth hormone
deficiency.
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency.
Accessed October 2019.
3 Turetsky, et al. Single cell imaging of Bruton's
Tyrosine Kinase using an irreversible inhibitor. Scientific
Reports. volume 4, Article number: 4782 (2014).
4 de Rooij MF, Kuil A, Geest CR, et al. The clinically
active BTK inhibitor PCI-32765 targets B-cell receptor- and
chemokine-controlled adhesion and migration in chronic lymphocytic
leukemia. Blood. 2012;119(11):2590-2594.
5 IMBRUVICA U.S. Prescribing
Information, September 2019.
View original
content:http://www.prnewswire.com/news-releases/abbvie-submits-supplemental-new-drug-application-to-us-fda-for-imbruvica-ibrutinib-in-combination-with-rituximab-for-the-treatment-of-previously-untreated-younger-adults-with-chronic-lymphocytic-leukemia-300954472.html
SOURCE AbbVie