Celgene Corporation (NASDAQ: CELG) and the Lymphoma Study
Association (LYSA) today announced that the Lymphoma Academic
Research Organisation (LYSARC) reported initial data from a phase
III, randomized, double-blind, international clinical study
(REMARC). This investigational study evaluated maintenance therapy
with REVLIMID® (lenalidomide) compared with placebo in
diffuse large B-cell lymphoma (DLBCL) patients responding to
first-line rituximab plus CHOP chemotherapy (R-CHOP) induction
therapy. LYSARC sponsored the study under a Clinical Trial
Agreement with Celgene.
REMARC achieved the primary endpoint of a statistically
significant improvement in progression-free survival for patients
receiving REVLIMID®. The interim analysis of overall
survival, a key secondary endpoint, showed no benefit in the
REVLIMID® arm. Based upon these interim results, Celgene
does not currently plan to seek approval for this indication.
“We thank the patients and their families for participating in
the REMARC trial and look forward to presenting these important
data at a future hematology conference,” said Bertrand Coiffier,
Professor of Hematology, Hospices de Lyon and University Claude
Bernard Lyon 1 and Principal Investigator, REMARC.
“We are continuing to partner with LYSA to complete the analyses
of the REMARC study,” said Michael Pehl, President Hematology and
Oncology of Celgene. “We remain committed to finishing the four
ongoing phase III trials evaluating REVLIMID® and are
confident about its potential as a treatment option across
different settings in lymphoma.”
A Broad Phase III Program in NHL Underway; Data from
Additional Trials Expected in 2017
The REMARC study is part of a broad research program at Celgene
focused on multiple areas of non-Hodgkin lymphoma. In addition to
the REMARC study, REVLIMID® is also being evaluated in:
- RELEVANCE®, a combination with
rituximab in previously untreated follicular lymphoma;
- AUGMENT®, a combination with
rituximab in relapsed/refractory follicular and marginal zone
lymphoma;
- MAGNIFY®, a combination with
rituximab in relapsed/refractory follicular, marginal zone and
mantle cell lymphoma; and,
- ROBUST®, a combination with
R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE® and AUGMENT® are expected in
the first and second half of 2017, respectively. Beyond
REVLIMID®, Celgene is also exploring multiple clinical
candidates in non-Hodgkin lymphomas and T-cell lymphomas.
REVLIMID® is not approved for use in DLBCL.
About REMARC
REMARC is an international, multicentre, randomized,
double-blind, placebo-controlled phase III study designed to
explore the effect of maintenance therapy with REVLIMID®
(lenalidomide) versus placebo on progression-free survival (PFS) in
650 patients treated with R-CHOP responding to induction therapy.
Patients in REMARC had received at least 6 and up to 8 cycles of
the R-CHOP 14 or R-CHOP 21 regimen or 6 R-CHOP-14 or -21 completed
by 2 cycles of rituximab alone in accordance to local preferences.
Evaluation of the response to R-CHOP was in accordance with Revised
Response Criteria for Malignant Lymphoma (2007). The primary
endpoint of the study was progression-free survival. The secondary
endpoints of the study included overall survival, event-free
survival, response at the end of maintenance, improvement in
response and safety.
About REVLIMID®
In the United States, REVLIMID® is approved in
combination with dexamethasone for the treatment of patients with
multiple myeloma. REVLIMID® is also approved in combination
with dexamethasone for the treatment of patients with multiple
myeloma who have received at least one prior therapy in nearly 70
countries, encompassing Europe, the Americas, the Middle East and
Asia, and in combination with dexamethasone for the treatment of
patients whose disease has progressed after one therapy in
Australia and New Zealand.
REVLIMID® is also approved in the United States, Canada,
Switzerland, Australia, New Zealand and several Latin American
countries, as well as Malaysia and Israel, for
transfusion-dependent anemia due to low- or intermediate-1-risk
myelodysplastic syndromes (MDS) associated with a deletion 5q
cytogenetic abnormality with or without additional cytogenetic
abnormalities and in Europe for the treatment of patients with
transfusion-dependent anemia due to low- or intermediate-1-risk MDS
associated with an isolated deletion 5q cytogenetic abnormality
when other therapeutic options are insufficient or inadequate.
In addition, REVLIMID® is approved in the United States
for the treatment of patients with mantle cell lymphoma (MCL) whose
disease has relapsed or progressed after two prior therapies, one
of which included bortezomib.
U.S. Regulatory Information for REVLIMID®
REVLIMID® (lenalidomide) in combination with
dexamethasone (dex) is indicated for the treatment of patients with
multiple myeloma (MM)
REVLIMID® is indicated for the treatment of
patients with transfusion-dependent anemia due to low-or
intermediate-1–risk myelodysplastic syndromes (MDS) associated with
a deletion 5q cytogenetic abnormality with or without additional
cytogenetic abnormalities
REVLIMID® is indicated for the treatment of
patients with mantle cell lymphoma (MCL) whose disease has relapsed
or progressed after two prior therapies, one of which included
bortezomib
REVLIMID® is not indicated and is not
recommended for the treatment of patients with chronic lymphocytic
leukemia (CLL) outside of controlled clinical trials
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY,
HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL
THROMBOEMBOLISM
Embryo-Fetal
Toxicity
Do not use REVLIMID®
during pregnancy. Lenalidomide, a thalidomide analogue, caused
limb abnormalities in a developmental monkey study. Thalidomide is
a known human teratogen that causes severe life-threatening human
birth defects. If lenalidomide is used during pregnancy, it may
cause birth defects or embryo-fetal death. In females of
reproductive potential, obtain 2 negative pregnancy tests before
starting REVLIMID® treatment. Females of reproductive
potential must use 2 forms of contraception or continuously abstain
from heterosexual sex during and for 4 weeks after
REVLIMID® treatment. To avoid embryo-fetal exposure
to lenalidomide, REVLIMID® is only available through
a restricted distribution program, the REVLIMID®
REMS® program (formerly known as the
“RevAssist®” program).
Information about the
REVLIMID® REMS® program is available
at www.celgeneriskmanagement.com or by calling the
manufacturer’s toll-free number 1-888-423-5436.
Hematologic
Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID® can cause
significant neutropenia and thrombocytopenia. Eighty percent of
patients with del 5q MDS had to have a dose delay/reduction during
the major study. Thirty-four percent of patients had to have a
second dose delay/reduction. Grade 3 or 4 hematologic toxicity was
seen in 80% of patients enrolled in the study. Patients on therapy
for del 5q MDS should have their complete blood counts monitored
weekly for the first 8 weeks of therapy and at least monthly
thereafter. Patients may require dose interruption and/or
reduction. Patients may require use of blood product support and/or
growth factors.
Venous and
Arterial Thromboembolism
REVLIMID® has
demonstrated a significantly increased risk of deep vein thrombosis
(DVT) and pulmonary embolism (PE), as well as risk of myocardial
infarction and stroke in patients with MM who were treated with
REVLIMID® and dexamethasone therapy. Monitor for and
advise patients about signs and symptoms of thromboembolism. Advise
patients to seek immediate medical care if they develop symptoms
such as shortness of breath, chest pain, or arm or leg swelling.
Thromboprophylaxis is recommended and the choice of regimen should
be based on an assessment of the patient’s underlying
risks.
CONTRAINDICATIONS
Pregnancy: REVLIMID® can cause fetal harm when
administered to a pregnant female and is contraindicated in females
who are pregnant. 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 the fetus
Allergic Reactions: REVLIMID® is contraindicated
in patients who have demonstrated hypersensitivity (e.g.,
angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis)
to lenalidomide
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See Boxed WARNINGS
- Females of
Reproductive Potential: See Boxed WARNINGS
- Males:
Lenalidomide is present in the semen of patients receiving the
drug. Males must always use a latex or synthetic condom during any
sexual contact with females of reproductive potential while taking
REVLIMID® and for up to 28 days after discontinuing
REVLIMID®, even if they have undergone a successful
vasectomy. Male patients taking REVLIMID® must not donate
sperm
- Blood
Donation: Patients must not donate blood during treatment
with REVLIMID® and for 1 month following discontinuation of
the drug because the blood might be given to a pregnant female
patient whose fetus must not be exposed to REVLIMID®
REVLIMID® REMS® Program:
See Boxed WARNINGS: Prescribers and pharmacies must be
certified with the REVLIMID® REMS® program by
enrolling and complying with the REMS requirements; pharmacies must
only dispense to patients who are authorized to receive
REVLIMID®. Patients must sign a Patient-Physician Agreement
Form and comply with REMS requirements; female patients of
reproductive potential who are not pregnant must comply with the
pregnancy testing and contraception requirements and males must
comply with contraception requirements
Hematologic Toxicity: REVLIMID® can cause
significant neutropenia and thrombocytopenia. Monitor patients with
neutropenia for signs of infection. Advise patients to observe for
bleeding or bruising, especially with use of concomitant
medications that may increase risk of bleeding. MM: Patients taking REVLIMID®/dex
should have their complete blood counts (CBC) assessed every 7 days
for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28
days thereafter. MDS: Patients
on therapy for del 5q MDS should have their complete blood counts
monitored weekly for the first 8 weeks of therapy and at least
monthly thereafter. Patients may require dose interruption and/or
dose reduction. Please see the Black Box WARNINGS for
further information. MCL:
Patients taking REVLIMID® for MCL should have their CBCs
monitored weekly for the first cycle (28 days), every 2 weeks
during cycles 2-4, and then monthly thereafter. Patients may
require dose interruption and/or dose reduction
Venous and Arterial Thromboembolism: See Boxed WARNINGS:
Venous thromboembolic events (DVT and PE) and arterial thromboses
(MI and CVA) are increased in patients treated with
REVLIMID®. Patients with known risk factors, including prior
thrombosis, may be at greater risk and actions should be taken to
try to minimize all modifiable factors (e.g., hyperlipidemia,
hypertension, smoking). Thromboprophylaxis is recommended and
regimen is based on patients underlying risks. ESAs and estrogens
may further increase the risk of thrombosis and their use should be
based on a benefit-risk decision
Increased Mortality in Patients With CLL: In a clinical
trial in the first line treatment of patients with CLL, single
agent REVLIMID® therapy increased the risk of death as
compared to single agent chlorambucil. Serious adverse
cardiovascular reactions, including atrial fibrillation, myocardial
infarction, and cardiac failure, occurred more frequently in the
REVLIMID® arm. REVLIMID® is not indicated and not
recommended for use in CLL outside of controlled clinical
trials
Second Primary Malignancies (SPM): In clinical trials in
patients with MM receiving REVLIMID®, an increase of
invasive SPM notably AML and MDS have been observed. Monitor
patients for the development of SPMs. Take into account both the
potential benefit of REVLIMID® and risk of SPMs when
considering treatment
Hepatotoxicity: Hepatic failure, including fatal cases,
has occurred in patients treated with REVLIMID®/dex.
Pre-existing viral liver disease, elevated baseline liver enzymes,
and concomitant medications may be risk factors. Monitor liver
enzymes periodically. Stop REVLIMID® upon elevation of liver
enzymes. After return to baseline values, treatment at a lower dose
may be considered
Allergic Reactions: Angioedema and serious dermatologic
reactions including Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) have been reported. These events can be
fatal. Patients with a prior history of Grade 4 rash associated
with thalidomide treatment should not receive REVLIMID®.
REVLIMID® interruption or discontinuation should be
considered for Grade 2-3 skin rash. REVLIMID® must be
discontinued for angioedema, Grade 4 rash, exfoliative or bullous
rash, or if SJS or TEN is suspected and should not be resumed
following discontinuation for these reactions. REVLIMID®
capsules contain lactose; risk-benefit of treatment should be
evaluated in patients with lactose intolerance
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have
been reported during treatment with lenalidomide. The patients at
risk of TLS are those with high tumor burden prior to treatment.
These patients should be monitored closely and appropriate
precautions taken
Tumor Flare Reaction (TFR): TFR has occurred during
investigational use of lenalidomide for CLL and lymphoma.
Monitoring and evaluation of TFR is recommended in patients with
MCL. Tumor flare may mimic the progression of disease (PD). In
patients with Grade 3 or 4 TFR, it is recommended to withhold
treatment with REVLIMID® until TFR resolves to ≤ Grade 1.
REVLIMID® may be continued in patients with Grade 1 and 2
TFR without interruption or modification, at the physician’s
discretion
Impaired Stem Cell Mobilization: A decrease in the number
of CD34+ cells collected after treatment (> 4 cycles) with
REVLIMID® has been reported. Consider early referral to
transplant center to optimize timing of the stem cell
collection
ADVERSE REACTIONS
Multiple Myeloma
- In newly diagnosed: The most
frequently reported Grade 3 or 4 reactions included neutropenia,
anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain,
hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT,
hyperglycemia, and leukopenia. The highest frequency of infections
occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%).
There were more grade 3 and 4 and serious adverse reactions of
infection in Arm Rd Continuous than either Arm MPT or RD18
- The most common adverse reactions
reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%),
neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%),
insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%),
dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms
(20%), and thrombocytopenia (20%)
- After at least one prior therapy
the most common adverse reactions reported in ≥20%
(REVLIMID®/dex vs dex/placebo): fatigue (44% vs 42%),
neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39%
vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia
(28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%),
back pain (26% vs 19%), upper respiratory tract infection (25% vs
16%), dyspnea (24% vs 17%), dizziness (23% vs 17%),
thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs
7%), and weight decreased (20% vs 15%)
Myelodysplastic
Syndromes
- Grade 3 and 4 adverse events reported
in ≥ 5% of patients with del 5q MDS were neutropenia (53%),
thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%),
leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain
(5%)
- Adverse events reported in ≥15% of del
5q MDS patients (REVLIMID®): thrombocytopenia (61.5%),
neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%),
fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis
(23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral
edema (20%), cough (20%), dizziness (20%), headache (20%), muscle
cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%),
asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma
- Grade 3 and 4 adverse events reported
in ≥5% of patients treated with REVLIMID® in the MCL trial
(N=134) included neutropenia (43%), thrombocytopenia (28%), anemia
(11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea
(6%), dyspnea (6%), and febrile neutropenia (6%)
- Adverse events reported in ≥15% of
patients treated with REVLIMID® in the MCL trial included
neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia
(31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%),
rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%),
constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS
Periodic monitoring of digoxin plasma levels is recommended due
to increased Cmax and AUC with concomitant REVLIMID®
therapy. Patients taking concomitant therapies such as
erythropoietin stimulating agents or estrogen containing therapies
may have an increased risk of thrombosis. It is not known whether
there is an interaction between dex and warfarin. Close monitoring
of PT and INR is recommended in MM patients taking concomitant
warfarin
NURSING MOTHERS
Discontinue drug or nursing taking into consideration the
importance of the drug to the mother
PEDIATRIC USE
Safety and effectiveness in patients below the age of 18 have
not been established
RENAL IMPAIRMENT
REVLIMID® is primarily excreted unchanged by the kidneys;
adjustments to the starting dose are recommended to provide
appropriate drug exposure in patients with moderate or severe renal
impairment and in patients on dialysis
Please see full Prescribing Information,
including Boxed WARNINGS.
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey,
is an integrated global biopharmaceutical company engaged primarily
in the discovery, development and commercialization of innovative
therapies for the treatment of cancer and inflammatory diseases
through next-generation solutions in protein homeostasis,
immuno-oncology, epigenetics, immunology and neuro-inflammation.
For more information, please visit www.celgene.com. Follow
Celgene on Social
Media: @Celgene, Pinterest, LinkedIn, FaceBook and YouTube.
About LYSARC
The Lymphoma Academic Research Organisation (LYSARC), located in
Lyon, France, is an academic clinical research organization running
international clinical lymphoma trials in affiliation with the LYSA
and in collaboration with other renowned, international cooperative
groups. For more information, please visit www.lysarc.org.
About LYSA
The Lymphoma Study Association (LYSA), is a French association
leader in international clinical and translational research in
lymphoma, with a network of 130 centers in France, Switzerland,
Portugal and Belgium. For more information, please visit
www.lysa-lymphoma.org
Forward-Looking Statements
This press release contains forward-looking statements, which
are generally statements that are not historical facts.
Forward-looking statements can be identified by the words
"expects," "anticipates," "believes," "intends," "estimates,"
"plans," "will," “outlook” and similar expressions. Forward-looking
statements are based on management’s current plans, estimates,
assumptions and projections, and speak only as of the date they are
made. We undertake no obligation to update any forward-looking
statement in light of new information or future events, except as
otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to
predict and are generally beyond our control. Actual results or
outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, many of which are discussed in more detail in our Annual
Report on Form 10-K and our other reports filed with the Securities
and Exchange Commission.
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For
Celgene:Investors:908-673-9628investors@celgene.comorMedia:908-673-2275media@celgene.comorFor
LYSA/LYSARC:Pascal Deschaseaux, General Manager, LYSARC+33 (0)4 72
66 38 67pascal.deschaseaux@lysarc.org
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