SUMMIT, N.J. - Thursday, August 21st 2014
Celgene Corporation (NASDAQ:CELG) today announced that results of a study evaluating the combination of REVLIMID® (lenalidomide) with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone (R-CHOP) in untreated diffuse large b-cell lymphoma (DLBCL) were published online ahead of print in the Journal of Clinical Oncology.
In a phase II, open label, single arm study, by Dr. Grzegorz Nowakowski of the Mayo Clinic, 64 patients with newly diagnosed, untreated, stage II-IV CD20 positive DLBCL received 25 mg of lenalidomide on days 1-10 with standard dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day two of each cycle and aspirin prophylaxis throughout. The primary endpoint was event-free survival (EFS) with secondary endpoints of progression free survival (PFS) and overall survival (OS). A one-stage binomial design was used to assess the efficacy and tolerability of REVLIMID with R-CHOP.
Of the 64 patients enrolled, 60 were eligible for response evaluation. In these patients, the overall response (OR) rate was 98% (59/60) with 80% (48/60) achieving a complete response (CR). The 24-month EFS, which was identical to PFS, and OS rates were 59% (48-74%) and 78% (68-90%), respectively (95% CI).
DLBCL molecular sub-type was determined by tumor immunohistochemistry (Hans algorithm) and classified as germinal center B-cell (GCB) vs. non-GCB. Additionally, 87 consecutive control patients from the Mayo Clinic Lymphoma Database who received conventional R-CHOP and who met the same inclusion criteria as R2CHOP treated patients were identified and analyzed for outcome based on DLBCL sub-types.
In the R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% vs. 64%, p<0.001 and 46% vs. 78%, p<0.001 in non-GCB patients vs. GCB patients, respectively. In patients treated with R2CHOP, the 24-month PFS and OS rates were 60% vs. 59%, p=0.83 and 83% vs. 75%, p=0.61 in non-GCB patients vs. GCB patients, respectively.
The most common grade 3 or higher adverse events in the study were neutropenia (87%), leukopenia (80%), thrombocytopenia (44%), anemia (16%) and febrile neutropenia (9%). Thrombosis was reported in one patient and there was one death in the study from perforation/sepsis.
“This study demonstrated that the addition of lenalidomide to conventional R-CHOP resulted in similar PFS rates and OS rates between sub-types,” said Dr. Nowakowski. “This is intriguing as patients with the non-GCB phenotype have traditionally experienced poorer outcomes. The results of this study support further evaluation of this regimen in this sub-type of DLBCL.”
The full manuscript of the publication can be found at http://jco.ascopubs.org/content/early/recent?home-right. Additionally, findings from a study on behalf of the Fondazione Italiana Linfomi evaluating lenalidomide plus R-CHOP21 in elderly patients with untreated DLBCL was published online ahead of print on May 13 in The Lancet (http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70191-3/abstract)
These studies build upon multiple trials evaluating combinations of lenalidomide and rituximab across non-Hodgkin’s lymphoma subtypes and helps support a broad phase III program at Celgene investigating combinations including lenalidomide and rituximab.
In DLBCL, REMARC, the company’s phase III study of lenalidomide maintenance compared with placebo following R-CHOP therapy completed enrollment in the first quarter of 2014. Also, ROBUST (DCL-002), the company’s pivotal phase III study evaluating lenalidomide plus R-CHOP21, is planned to start enrollment in the first quarter of 2015. Celgene also commenced a collaboration with NanoString Technologies this year to develop a companion biomarker diagnostic for purposes of classifying patient subtypes in the study. Further, the Eastern Cooperative Oncology Group (ECOG) is also enrolling patients to a phase II study of R2CHOP compared with R-CHOP in untreated DLBCL.
In follicular lymphoma, the company expects to complete enrollment of RELEVANCE, its phase III study of lenalidomide plus rituximab compared with rituximab plus chemotherapy in patients with previously untreated disease in the second half of 2014. Additionally, enrollment began earlier this year for AUGMENT, a phase III, double-blind study of lenalidomide plus rituximab compared with rituximab plus placebo in relapsed or refractory patients. Finally, the company will investigate the optimal dose and schedule of this regimen through MAGNIFY, evaluating lenalidomide plus rituximab followed by rituximab maintenance in patients with follicular, marginal zone and mantle cell lymphoma.
REVLIMID is not approved for the treatment of patients with follicular lymphoma or diffuse large b-cell lymphoma.
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 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 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.
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 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
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 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
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 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
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. 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.
Contacts
Celgene Corporation
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