BOUDRY, Switzerland--(BUSINESS WIRE)--Celgene International Sàrl (Nasdaq: CELG) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA) today announced the organizations have initiated an international, Phase III, open-label, randomized study to evaluate the therapeutic potential of a novel chemotherapy-free approach for the treatment of follicular lymphoma (FL). The combination of REVLIMID (lenalidomide) and rituximab, also referred to as the R-squared (or R2) regimen pioneered by Nathan Fowler, MD and colleagues at the MD Anderson Cancer Center, Houston TX, will be investigated in a study of up to 1,000 patients with newly diagnosed FL. GELA is considered a leading cooperative group for studying the treatment of adult lymphoma patients, and its work has helped establish the standard of care in the treatment of FL as well as other lymphomas.
The RELEVANCE study looks to advance the treatment of patients diagnosed with FL, a form of non-Hodgkin's lymphoma (NHL). FL represents the second most common lymphoma, with approximately 25,000 new cases diagnosed per year in the United States and Europe combined. The clinical benefits of REVLIMID as a single agent and in combination with rituximab continue to be reported in peer-reviewed publications and at major international medical meetings.
"REVLIMID, both as a monotherapy and in combination with rituximab, is demonstrating encouraging activity in patients with variety of lymphoma subtypes," said Franck Morschhauser, Professor of Hematology at the Hôpital Claude Huriez in Lille, France. “We are especially excited by the fact that REVLIMID may not only act as an immunomodulatory agent with direct and indirect cancer activity, but may also enhance the activity of rituximab against cancer cells through a process we call antibody dependant cell-mediated cytotoxicity (ADCC).”
“If positive, this study could represent a true advance in novel therapies for patients with follicular lymphoma, an incurable sub-type of the disease,” said Jean Pierre Bizzari, M.D., Head of Global Clinical Oncology/Hematology for Celgene Corporation. “We are pleased to be collaborating with GELA on this important study, as well as the REMARC trial of REVLIMID maintenance following R-CHOP in elderly patients with diffuse large B-cell lymphoma.”
RELEVANCE is being conducted as two companion studies: RV-FOL-GELARC-0683 outside of the United States (F Morschhauser, M.D., coordinating investigator) and RV-FOL-GELARC-0683C within the United States (Nathan Fowler, M.D., MD Anderson Cancer Center, Houston, TX, USA, coordinating investigator). In each study, previously untreated FL patients will be randomized to receive either R2 (six 28-day cycles) or rituximab plus chemotherapy (CHOP, eight 21-day cycles; CVP, eight 21-day cycles; or bendamustine, six 28-day cycles). Following induction therapy, patients in the R2 arm will receive maintenance therapy with REVLIMID for one year and rituximab for two years. Patients in the chemotherapy arm will receive two years of rituximab maintenance. This experimental regimen is based on the results of an earlier clinical trial conducted at MD Anderson (Fowler; abstract 137, ICML 2011)
The primary objectives of the study are to assess the complete response rates and progression-free survival in patients receiving R2 and those receiving rituximab plus chemotherapy. The secondary objectives include assessments of event-free survival, overall survival, overall response rate, health-related quality of life, and safety in both groups of patients. The combined total of 1,000 subjects enrolled in both studies will be evaluated in the final analysis. All patients will be followed for disease progression and overall survival for up to 10 years.
About Follicular Lymphoma
Follicular lymphoma is a common type of non-Hodgkin's lymphoma (NHL), accounting for about one in four of all cases. It affects as many men as it does women and can occur at any time during adulthood, although patients are typically diagnosed in their sixties. It is a low-grade lymphoma, which means that while it usually develops slowly, the disease is considered incurable, as nearly all patients who respond to initial treatment will ultimately relapse.
About ADCC (antibody-dependent cell-mediated cytotoxicity)
ADCC is an immune defense mechanism that directs natural killer cells, T cells, macrophages and other immune cells to cause cancer cell death. Antibodies such as rituximab target receptors on lymphoma cells to induce ADCC. In addition to being an immunomodulatory agent with direct and indirect cancer activity, REVLIMID may also enhance the ADCC process against cancer cells.
About GELA (Groupe d’Etude des Lymphomes de l’Adulte)
GELA is a European cooperative group of physicians performing clinical and translational research in the area of lymphoma. GELA is actively cooperating with other lymphoma cooperative groups in the world. GELA delegates the organization or the clinical trials to the academic clinical research organization GELARC (Groupe d’Etude des Lymphomes de l’Adulte). GELARC will coordinate the trial worldwide.
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, Japan 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. Marketing Authorization Applications are currently being evaluated in a number of other countries.
Important U.S. Safety Information
REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy.
REVLIMID is indicated for patients with transfusion-dependent anaemia due to Low- or Intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
Important Safety Information
WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
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 death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid fetal exposure to lenalidomide, REVLIMID is only available under a restricted distribution program called “RevAssist®.”
Information about the RevAssist program is available at www.REVLIMID.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. (see DOSAGE and ADMINISTRATION)
DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
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 thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.
CONTRAINDICATIONS:
Pregnancy Category X:
- Lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. Females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy
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:
Fetal Risk:
- REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates 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. If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby
- Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used during therapy, during therapy interruptions, and for at least 4 weeks after completing therapy
- Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy
Reproductive Risk and Special Prescribing Requirements (RevAssist Program):
- Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available, in the United States, under a special restricted distribution program called “RevAssist.” Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and meet all the conditions of the RevAssist program
Haematologic Toxicity—Multiple Myeloma:
- REVLIMID can cause significant neutropenia and thrombocytopenia
- 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 studies Grade 3 and 4 haematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone
- Patients may require dose interruption and/or dose reduction
Deep Vein Thrombosis:
- 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 treated with lenalidomide monotherapy
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
Tumour Lysis Syndrome:
- Fatal instances of tumour lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken
Tumour Flare Reaction:
- Tumour flare reaction has occurred during investigational use of lenalidomide for chronic lymphocytic leukaemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged
DRUG INTERACTIONS:
- Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as oestrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone
USE IN SPECIAL POPULATIONS:
Nursing Mothers:
- It is not known whether REVLIMID is excreted in human milk
- 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
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 or severe renal impairment (CLcr < 60 mL/min) and in patients on dialysis
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, 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
- 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%), diarrhoea (39% vs. 27%), muscle cramp (33% vs. 21%), anaemia (31% vs. 24%), pyrexia (28% vs. 23%), peripheral enema (26% vs. 21%), nausea (26% vs. 21%), back pain (26% vs. 19%), upper respiratory tract infection (25% vs. 16%), dyspnoea (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
- Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhoea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral oedema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnoea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
DOSAGE AND ADMINISTRATION:
-
Treatment is continued or modified based upon clinical and laboratory
findings. Dosing modifications are recommended to manage Grade 3 or 4
neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged
to be related to REVLIMID
- For other Grade 3 or 4 toxicities judged to be related to REVLIMID, hold treatment and restart at next lower dose level when toxicity has resolved to ≤Grade 2
Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.
About Celgene Risk-Management
Celgene continues to be a pioneer in creating environments in which patients who can benefit from our disease-altering therapies are able to do so, and do so safely. We are fully committed to drug lifecycle safety, from clinical development to post-marketing surveillance. As a result, patients worldwide continue to benefit from our risk-management programs such as, S.T.E.P.S.(R), RevAssist(R), RevMate(R) and PRMP, which form the global foundation of our commitment to patient safety.
About Celgene International Sàrl
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. 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.
This release contains certain forward-looking statements which involve known and unknown risks, delays, uncertainties and other factors not under the Company’s control. The Company’s actual results, performance, or achievements could be materially different from those projected by these forward-looking statements. The factors that could cause actual results, performance, or achievements to differ from the forward-looking statements are discussed in the Company’s filings with the Securities and Exchange Commission, such as the Company’s Form 10-K, 10-Q and 8-K reports. Given these risks and uncertainties, you are cautioned not to place undue reliance on the forward-looking statements.