Celgene Will Discontinue Phase III ORIGIN® Trial in Previously Untreated Elderly Patients with B-Cell Chronic Lymphocytic

  Celgene Will Discontinue Phase III ORIGIN® Trial in Previously Untreated
  Elderly Patients with B-Cell Chronic Lymphocytic Leukemia

Business Wire

SUMMIT, N.J. -- July 18, 2013

Celgene Corporation (NASDAQ: CELG) today announced that after consultation
with the U.S. Food and Drug Administration (FDA) Celgene will discontinue
treatment with REVLIMID^® (lenalidomide) in the open-label, phase III ORIGIN®
trial, which enrolled 450 patients in over 100 sites in 26 countries. An
imbalance was observed in the number of deaths in patients treated with
lenalidomide versus patients treated with chlorambucil.

The FDA placed the ORIGIN study on clinical hold on July 12, 2013, with the
discontinuation of lenalidomide treatment. All clinical investigators in
ongoing chronic lymphocytic leukemia studies using lenalidomide will be
officially advised of this action and instructed to inform their patients
accordingly.

REVLIMID is not approved as a treatment for patients with chronic lymphocytic
leukemia.

The ORIGIN study was designed to evaluate the efficacy and safety of
lenalidomide versus chlorambucil as single agent in elderly patients ≥ 65
years of age with B-cell chronic lymphocytic leukemia and with comorbidities
that precluded treatment with more aggressive standard chemo-immunotherapies,
including fludarabine and bendamustine containing regimens. The majority of
patients presented with multiple comorbidities, such as diabetes, congestive
heart failure, renal impairment and elevated bilirubin count.

Based on an imbalance in deaths, specifically 34 deaths out of 210 patients in
the lenalidomide arm compared to 18 deaths out of 211 patients in the
chlorambucil arm, FDA placed the study on clinical hold. No specific causality
for this imbalance has been identified to date.

Results from the CLL-008 study will be presented at an upcoming medical
conference.

All other Celgene-sponsored chronic lymphocytic leukemia clinical trials with
lenalidomide are continuing in accordance with their respective protocols.

About REVLIMID^®

REVLIMID is 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 approved in the United States, Canada, Switzerland, Australia, New
Zealand and several Latin American countries, as well as Malaysia and Israel,
for transfusion-dependent anaemia due to low- or intermediate-1-risk 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
myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic
abnormality when other therapeutic options are insufficient or inadequate.

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 is indicated for
the treatment of patients with multiple myeloma (MM) who have received at
least one prior therapy

REVLIMID^® (lenalidomide) 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^® (lenalidomide) 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

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS
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 Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein
thrombosis (DVT) and pulmonary embolism (PE) in patients with MM who were
treated with REVLIMID and dexamethasone therapy. Patients and physicians are
advised to be observant for the signs and symptoms of thromboembolism.
Patients should be instructed to seek medical care if they develop symptoms
such as shortness of breath, chest pain, or arm or leg swelling. It is not
known whether prophylactic anticoagulation or antiplatelet therapy prescribed
in conjunction with REVLIMID may lessen the potential for venous
thromboembolism. The decision to take prophylactic measures should be done
carefully after an assessment of an individual patient’s underlying risk
factors.

CONTRAINDICATIONS

Pregnancy:

  *REVLIMID can cause fetal harm when administered to a pregnant female.
    Lenalidomide 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:

  *REVLIMID is an analogue of thalidomide, a known human teratogen that
    causes life-threatening human birth defects or embryo-fetal death. An
    embryo-fetal development study in monkeys indicates that lenalidomide
    produced malformations in the offspring of female monkeys who received the
    drug during pregnancy, similar to birth defects observed in humans
    following exposure to thalidomide during pregnancy
  *Females of Reproductive Potential: Must avoid pregnancy for at least 4
    weeks before beginning REVLIMID therapy, during therapy, during dose
    interruptions and for at least 4 weeks after completing therapy. Must
    commit either to abstain continuously from heterosexual sexual intercourse
    or to use two methods of reliable birth control beginning 4 weeks prior to
    initiating treatment with REVLIMID, during therapy, during dose
    interruptions and continuing for 4 weeks following discontinuation of
    REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to
    initiating therapy
  *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

Because of embryo-fetal risk, REVLIMID is available only through a restricted
program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID
REMS Program (formerly known as the “RevAssist^®” Program). Prescribers and
pharmacies must be certified with the program and patients must sign an
agreement form and comply with the requirements. Further information about the
REVLIMID REMS program is available at www.celgeneriskmanagement.com or by
telephone at 1-888-423-5436

Hematologic Toxicity: REVLIMID can cause significant neutropenia and
thrombocytopenia. MM: Patients taking REVLIMID for MM should have their
complete blood counts monitored every 2 weeks for the first 12 weeks and then
monthly thereafter. In the pooled MM trials Grade 3 and 4 hematologic
toxicities were more frequent in patients treated with the combination of
REVLIMID and dexamethasone than in patients treated with dexamethasone alone.
MCL: Patients taking REVLIMID for MCL should have their complete blood counts
monitored weekly for the first cycle (28 days), every 2 weeks during cycles
2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia
was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was
reported in 28% of the patients. Patients may require dose interruption and/or
dose reduction

Venous Thromboembolism: Venous thromboembolic events (predominantly deep
venous thrombosis and pulmonary embolism) have occurred in patients with MM
treated with lenalidomide combination therapy and patients with MDS or MCL
treated with lenalidomide monotherapy. It is not known whether prophylactic
anticoagulation or antiplatelet therapy prescribed in conjunction with
REVLIMID may lessen the potential for venous thromboembolism. The decision to
take prophylactic measures should be done carefully after assessment of the
individual patient’s underlying risk factors

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 REVLIMID treatment should be evaluated in
patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (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: Tumor flare reaction (TFR) has occurred during
investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and
lymphoma, and is characterized by tender lymph node swelling, low grade fever,
pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored
clinical trial is discouraged

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 lenalidomide until TFR
resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects
experienced TFR; all reports were Grade 1 or 2 in severity. All of the events
occurred in cycle 1 and one patient developed TFR again in cycle 11.
Lenalidomide may be continued in patients with Grade 1 and 2 TFR without
interruption or modification, at the physician’s discretion. Patients with
Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal
anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of
TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of
symptoms per the guidance for treatment of Grade 1 and 2 TFR

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in
patients treated with lenalidomide in combination with dexamethasone. The
mechanism of drug-induced hepatotoxicity is unknown. 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

Second Primary Malignancies: Patients with MM treated with lenalidomide in
studies including melphalan and stem cell transplantation had a higher
incidence of second primary malignancies, particularly acute myelogenous
leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms
who received similar therapy but did not receive lenalidomide. Monitor
patients for the development of second malignancies. Take into account both
the potential benefit of lenalidomide and the risk of second primary
malignancies when considering treatment with lenalidomide

ADVERSE REACTIONS

Multiple Myeloma

  *In the REVLIMID/dexamethasone treatment group, 269 patients (76%)
    underwent at least one dose interruption with or without a dose reduction
    of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone
    treatment group
  *Of these patients who had one dose interruption with or without a dose
    reduction, 76% (269/353) vs 57% (199/350), 50% in the
    REVLIMID/dexamethasone treatment group underwent at least one additional
    dose interruption with or without a dose reduction compared to 21% in the
    placebo/dexamethasone treatment group
  *Most adverse events and Grade 3/4 adverse events were more frequent in MM
    patients who received the combination of REVLIMID/dexamethasone compared
    to placebo/dexamethasone
  *Grade 3/4 neutropenia occurred in 33.4% vs 3.4%; 2.3% experienced Grade
    3/4 febrile neutropenia vs 0%
  *Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction
    (7.4%) or Grade 3/4 (8.2%) compared to 3.1% and 3.4%. Discontinuations due
    to DVT were reported at comparable rates between groups
  *Pulmonary embolism (PE) was reported as a serious adverse drug reaction
    (3.7%) or Grade 3/4 (4.0%) compared to 0.9% and 0.9%. Discontinuations due
    to PE were reported at comparable rates between groups
  *Adverse reactions reported in ≥15% of MM patients (REVLIMID/dexamethasone
    vs dexamethasone/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%),
    weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision
    (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)

Myelodysplastic Syndromes

  *Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the
    most frequently reported adverse events observed in the del 5q MDS
    population
  *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%)
  *Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID):
    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%)
  *Serious adverse events reported in ≥2 patients treated with REVLIMID
    monotherapy for MCL included chronic obstructive pulmonary disease,
    clostridium difficile colitis, sepsis, basal cell carcinoma, and
    supraventricular tachycardia
  *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%)
  *Adverse events occurring in patients treated with REVLIMID in the MCL
    trial resulted in at least one dose interruption in 76 (57%) patients, at
    least one dose reduction in 51 (38%) patients, and discontinuation of
    treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical
judgment and based on standard clinical practice in patients receiving this
medication, is recommended during administration of REVLIMID. It is not known
whether there is an interaction between dexamethasone and warfarin. Close
monitoring of PT and INR is recommended in MM patients taking concomitant
warfarin. Erythropoietic agents, or other agents, that may increase the risk
of thrombosis, such as estrogen containing therapies, should be used with
caution in MM patients receiving lenalidomide with dexamethasone

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue
the drug. Under these conditions, refer patient to an
obstetrician/gynecologist experienced in reproductive toxicity for further
evaluation and counseling. Any suspected fetal exposure to REVLIMID must be
reported to the FDA via the MedWatch program at 1-800-332-1088 and also to
Celgene Corporation at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
adverse reactions in nursing infants, a decision should be made whether to
discontinue nursing or the drug, taking into account the importance of the
drug to the mother

Pediatric Use: Safety and effectiveness in pediatric patients below the age of
18 have not been established

Geriatric Use: Since elderly patients are more likely to have decreased renal
function, care should be taken in dose selection. Monitor renal function

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the
kidney, adjustments to the starting dose of REVLIMID are recommended to
provide appropriate drug exposure in patients with moderate (CLcr 30-60
mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on
dialysis

Please see full Prescribing Information, including Boxed WARNINGS,
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated
global pharmaceutical company engaged primarily in the discovery, development
and commercialization of innovative therapies for the treatment of cancer and
inflammatory diseases through gene and protein regulation. For more
information, please visit the Company's website at www.celgene.com.

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.

Contact:

For Celgene:
Investors:
908-673-9628
investors@celgene.com
or
Media:
908-673-2275
media@celgene.com
 
Press spacebar to pause and continue. Press esc to stop.