Final analysis showed highly statistically
significant improvement in progression-free survival for R2
compared with rituximab plus placebo
Global regulatory submissions planned in the
first quarter of 2019
Celgene Corporation (NASDAQ: CELG) today announced results from
a phase III, randomized, double-blind, international clinical study
(AUGMENT). REVLIMID® (lenalidomide) plus rituximab (R2) achieved a
highly statistically significant improvement in the primary
endpoint of progression-free survival (PFS), compared to rituximab
plus placebo, in the final PFS analysis.
AUGMENT evaluated the efficacy and safety of the investigational
combination of R2 versus rituximab plus placebo in patients (N=358)
with relapsed/refractory follicular and marginal zone lymphoma.
In addition to achieving the primary endpoint of the study, a
favorable trend was observed for overall survival (OS) during this
analysis and follow-up will continue for the mature OS results. The
safety profile of R2 was consistent with the known safety profiles
of the individual medicines, and no new safety signals were
identified with the combination.
“Indolent non-Hodgkin lymphomas, such as follicular lymphoma and
marginal zone lymphoma, are diseases of underlying immune
dysfunction with a need for new options beyond currently available
therapies,” said Jay Backstrom, M.D., Chief Medical Officer for
Celgene. “We are encouraged by the highly significant improvement
in progression-free survival observed in this study and look
forward to engaging with regulatory authorities as soon as
possible. The R2 regimen represents a potentially new
chemotherapy-free option for these patients.”
Data from AUGMENT will be submitted to a future medical meeting
and Celgene plans to prepare global regulatory submissions in the
first quarter of 2019.
REVLIMID® alone or in combination is not approved for use
in follicular lymphoma or marginal zone lymphoma in any
geography.
About REVLIMID®
REVLIMID® (lenalidomide) in combination with
dexamethasone (dex) is indicated for the treatment of patients with
multiple myeloma (MM)
REVLIMID is indicated as maintenance therapy in patients with
MM following autologous hematopoietic stem cell transplantation
(auto-HSCT)
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.
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 risk to the fetus
Severe Hypersensitivity Reactions: REVLIMID is
contraindicated in patients who have demonstrated severe
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 4 weeks 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 4 weeks 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 or
REVLIMID as maintenance therapy 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 the regimen should
be based on patient’s 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 hematologic
plus solid tumor SPM, notably AML and MDS, have been observed.
Monitor patients for the development of SPM. Take into account both
the potential benefit of REVLIMID and risk of SPM when considering
treatment
Increased Mortality with Pembrolizumab: In clinical
trials in patients with multiple myeloma, the addition of
pembrolizumab to a thalidomide analogue plus dexamethasone resulted
in increased mortality. Treatment of patients with multiple myeloma
with a PD-1 or PD-L1 blocking antibody in combination with a
thalidomide analogue plus dexamethasone is not recommended outside
of controlled clinical trials
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
Severe Cutaneous Reactions Including Hypersensitivity
Reactions: Angioedema and severe cutaneous reactions including
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),
and drug reaction with eosinophilia and systemic symptoms (DRESS)
have been reported. DRESS may present with a cutaneous reaction
(such as rash, or exfoliative dermatitis), eosinophilia, fever,
and/or lymphadenopathy with systemic complications such as
hepatitis, nephritis, pneumonitis, myocarditis, and/or
pericarditis. 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, TEN, or DRESS is suspected
and should not be resumed following discontinuation for these
reactions
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 for 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
Thyroid Disorders: Both hypothyroidism and
hyperthyroidism have been reported. Measure thyroid function before
start of REVLIMID treatment and during therapy
Early Mortality in Patients with MCL: In another MCL
study, there was an increase in early deaths (within 20 weeks),
12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk
factors for early deaths include high tumor burden, MIPI score at
diagnosis, and high WBC at baseline (≥10 x 109/L)
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%)
- Maintenance Therapy Post
Auto-HSCT: The most frequently reported Grade 3 or 4 reactions
in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and
leukopenia. The serious adverse reactions of lung infection and
neutropenia (more than 4.5%) occurred in the REVLIMID arm
- The most frequently reported adverse
reactions in ≥20% (REVLIMID arm) across both maintenance studies
(Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia
(72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper
respiratory tract infection (27%, 11%), bronchitis (5%, 47%),
nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%,
23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%),
asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%,
21%)
- 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 patients with MM taking concomitant
warfarin
USE IN SPECIFIC POPULATIONS
- PREGNANCY: See Boxed WARNINGS:
If pregnancy does occur during treatment, immediately discontinue
the drug and refer patient to an obstetrician/gynecologist
experienced in reproductive toxicity for further evaluation and
counseling. There is a REVLIMID pregnancy exposure registry that
monitors pregnancy outcomes in females exposed to REVLIMID during
pregnancy as well as female partners of male patients who are
exposed to REVLIMID. This registry is also used to understand the
root cause for the pregnancy. Report any suspected fetal exposure
to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088
and also to Celgene Corporation at 1-888-423-5436
- LACTATION: There is no
information regarding the presence of lenalidomide in human milk,
the effects of REVLIMID on the breastfed infant, or the effects of
REVLIMID on milk production. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in
breastfed infants from REVLIMID, advise female patients not to
breastfeed during treatment with REVLIMID
- PEDIATRIC USE: Safety and
effectiveness have not been established in pediatric patients
- RENAL IMPAIRMENT: Adjust the
starting dose of REVLIMID based on the creatinine clearance value
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.
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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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