Celgene Corporation
Dec 8, 2014
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Results from Phase III Study of REVLIMID® (Lenalidomide) Demonstrating Improved Transfusion Independence in Patients with Rare Blood Cancer, Non-Del-5Q Myelodysplastic Syndromes (MDS), Presented at ASH

Median duration of transfusion independence was 8.2 months

SAN FRANCISCO--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ:CELG) today announced results from an international phase III study of REVLIMID® (lenalidomide) compared with placebo in patients with red-blood cell (RBC) transfusion dependent low-risk myelodysplastic syndromes (MDS) who were unresponsive or refractory to erythropoietin stimulating agents (ESA) and did not have a deletion 5q cytogenic abnormality. The results were presented during the 56th American Society of Hematology (ASH) annual meeting.

The study, presented by Valeria Santini, M.D., found that significantly more patients treated with lenalidomide achieved RBC-transfusion independence of at least 56 days compared with placebo (26.9%, [43/160 patients] vs. 2.5%,[2/79 patients]; p < 0.001), the primary endpoint of the study. The majority of patients (90%) with transfusion independence responded within 16 weeks of treatment. For patients who became transfusion independent, the median duration of transfusion independence was 8.2 months (range 5.2-17.8). Additionally, transfusion independence of at least 168 days was reached in 17.5% (28/160) of patients receiving lenalidomide compared with no patients receiving placebo. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80-4.59) and 2.46 (95% CI 0.79-7.64) for lenalidomide and placebo patients, respectively. The follow-up period was not long enough to permit an overall survival comparison.

Myelosuppression was the main adverse event (AE). Grade 3-4 neutropenia occurred in 61.9% versus 12.7% in the lenalidomide and placebo groups, respectively, and grade 3-4 thrombocytopenia occurred in 35.6% versus 3.8% in the lenalidomide and placebo groups, respectively.

"This confirmation of the Phase II data is extremely encouraging. Based on this study, REVLIMID may offer this refractory patient population an additional option beyond their current limited choices," said Guillermo Garcia-Manero, M.D. of the M.D. Anderson Cancer Center at the University of Texas.

REVLIMID is not indicated for the treatment of non-del5q MDS in any country.

About MDS-005

In this multi-center, double-blind, parallel-group phase III study, patients were randomized 2:1 to oral lenalidomide, 10 mg once daily (5 mg for patients with creatinine clearance 40-60 mL/min) (n=160) versus placebo (n=79). Patients with transfusion independence of more than 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was transfusion independence of ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to transfusion independence, duration of transfusion independence, transfusion independence of ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of lenalidomide response.

About MDS

About REVLIMID®

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 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.

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 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

REVLIMID is not indicated and 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 dex 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:

Allergic Reactions:

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity:

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 dex 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. See Boxed WARNINGS

Venous and Arterial Thromboembolism: A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM treated with REVLIMID and dex compared to the placebo and dex group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM who were treated with REVLIMID and dex therapy compared with placebo and dex (0.6%, and 0.9%) in clinical trials. 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). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID and dex compared to 8.3% thrombosis in the placebo and dex group. Median time to first thrombosis event was 2.7 months. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS

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. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

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

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dex. 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

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 CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

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 and 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

ADVERSE REACTIONS

Multiple Myeloma

Myelodysplastic Syndromes

Mantle Cell Lymphoma

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 dex 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 after making a benefit-risk assessment in patients receiving REVLIMID

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.

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 www.celgene.com. Follow us on Twitter @Celgene as well.

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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