CLINICAL NEWS radiation therapy , or investigation drugs within four weeks of study treatment ; or used corticosteroids within one week of first study dose .
Patients received 420 mg of ibrutinib once daily continuously until disease progression or unacceptable toxicity . Treatment response was assessed with computed tomography radiologic examination at the end of weeks nine , 17 , 25 , 37 , 49 , 61 , 73 , and 85 , and
Males Lenalidomide is present in the semen of males who take REVLIMID . Therefore , males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID , during dose interruptions 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
8.7 Renal Impairment Since lenalidomide 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 [ see Dosage and Administration ( 2.4 )].
8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment . The elimination of unchanged lenalidomide is predominantly by the renal route .
10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM , MDS , or MCL . In dose-ranging studies in healthy subjects , some were exposed to up to 200 mg ( administered 100 mg BID ) and in single-dose studies , some subjects were exposed to up to 400 mg . Pruritus , urticaria , rash , and elevated liver transaminases were the primary reported AEs . In clinical trials , the dose-limiting toxicity was neutropenia and thrombocytopenia .
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted .
Lenalidomide was not mutagenic in the bacterial reverse mutation assay ( Ames test ) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes , or mutations at the thymidine kinase ( tk ) locus of mouse lymphoma L5178Y cells . Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats .
A fertility and early embryonic development study in rats , with administration of lenalidomide up to 500 mg / kg ( approximately 200 times the human dose of 25 mg , based on body surface area ) produced no parental toxicity and no adverse effects on fertility .
17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling ( Medication Guide )
Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [ see Contraindications ( 4.1 )]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )].
• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy .
• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test .
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy , during dose interruption and for 4 weeks after she has completely finished taking REVLIMID . Highly effective forms of contraception other than tubal ligation include IUD and hormonal ( birth control pills , injections , patch or implants ) and a partner ’ s vasectomy . Additional effective contraceptive methods include latex or synthetic condom , diaphragm and cervical cap .
• Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug , if she misses her menstrual period , or experiences unusual menstrual bleeding , if she stops taking birth control , or if she thinks FOR ANY REASON that she may be pregnant .
• Advise patient that if her doctor is not available , she can call 1-888-668-2528 for information on emergency contraception [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )].
• Advise males to 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 .
• Advise male patients taking REVLIMID that they must not donate sperm [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )]. every 24 weeks thereafter until disease progression .
The ORR of 64 percent was reported by an independent review committee ( n = 92 ; 95 % CI 56-71 ).
Dr . O ’ Brien and authors reported an ORR of 83 percent ( n = 120 ; 95 % CI 76- 89 ) in a post-hoc , investigator-extended assessment with a median follow-up of 27.6 months ( IQR = 14.6-27.7 months ), The 24-month , progression-free survival
( PFS ) rate was 63 percent ( 95 % CI 54- 70 %) and the 24-month , overall survival rate was 75 percent ( 95 % CI , 67-81 %), but the median PFS and OS were not reached .
Seventy-nine percent of patients without cytopenia at baseline ( n = 72 / 91 ) experienced sustained hematologic improvement ( defined as ≥50 % increase over baseline or improvement to absolute neutrophil count > 1.5 cells × 10⁹ / L , hemoglobin
• All patients must be instructed to not donate blood while taking REVLIMID , during dose interruptions and for 1 month following discontinuation of REVLIMID [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )].
REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity , REVLIMID is only available through a restricted program called the REVLIMID REMS™ program ( formerly known as the “ RevAssist ® ” program ) [ see Warnings and Precautions ( 5.2 )].
• Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID . In particular , females of reproductive potential must comply with the pregnancy testing , contraception requirements and participate in monthly telephone surveys . Males must comply with the contraception requirements [ see Use in Specific Populations ( 8.6 )].
• REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program . Provide patients with the telephone number and website for information on how to obtain the product .
Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [ see Boxed Warnings and Warnings and Precautions ( 5.3 )].
Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT , PE , MI , and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [ see Boxed Warnings and Warning and Precautions ( 5.4 )].
Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions , including atrial fibrillation , myocardial infarction , and cardiac failure [ see Warning and Precautions ( 5.5 )].
Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [ see Warnings and Precautions ( 5.6 )].
Hepatotoxicity Inform patients of the risk of hepatotoxicity , including hepatic failure and death , and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [ see Warnings and Precautions ( 5.7 )].
Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity , angioedema , Stevens-Johnsons Syndrome , or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [ see Warnings and Precautions ( 5.8 )].
Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [ see Warnings and Precautions ( 5.9 )].
Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [ see Warnings and Precautions ( 5.10 )].
Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day , either with or without food . The capsules should not be opened , broken , or chewed . REVLIMID should be swallowed whole with water .
Instruct patients that if they miss a dose of REVLIMID , they may still take it up to 12 hours after the time they would normally take it . If more than 12 hours have elapsed , they should be instructed to skip the dose for that day . The next day , they should take REVLIMID at the usual time . Warn patients to not take 2 doses to make up for the one that they missed .
Manufactured for :
Celgene Corporation Summit , NJ 07901
REVLIMID ® , RevAssist ® , and THALOMID ® are registered trademarks of Celgene Corporation .
REVLIMID REMS™ is a trademark of Celgene Corporation . Pat . www . celgene . com / therapies
© 2005-2015 Celgene Corporation , All Rights Reserved . REV _ MM _ HCP _ BS _ v020 02 _ 2015
> 110 g / L , or platelets > 100 cells × 10⁹ / L that was sustained continuously for ≥56 days without a need for blood transfusion or growth factors ).
The median duration of response ( a secondary endpoint ) also was not reached .
Half of the patients ( n = 72 ) discontinued ibrutinib . The most common reasons for treatment discontinuation were progressive disease ( n = 34 ; 24 %) and adverse events , unacceptable toxicity , or death ( n = 24 ; 17 %). In addition , 9 percent of patients experienced major bleeding .
Common grade 3 – 5 treatment-emergent adverse events ( occurring in ≥5 % of patients ) were : neutropenia ( n = 24 ; 18 %), pneumonia ( n = 19 ; 13 %), hypertension ( n = 18 ; 13 %), thrombocytopenia ( n = 12 ; 8 %), anemia ( n = 14 ; 10 %), and atrial fibrillation ( n = 8 ; 6 %).
Ten patients ( 7 %) underwent dose reductions of ibrutinib from 420 mg to 280 mg and four ( 3 %) underwent dose reductions to 140 mg due to adverse events . The most common adverse events leading to dose reductions were pneumonia and spontaneous hematoma ( two patients each ).
Among the patients who had dose reductions , eight remained on treatment and six discontinued ( three because of progressive disease and three because of adverse events ).
“ The safety profile of ibrutinibtreated patients in this study was consistent with previous reports , with most adverse events being mild to moderate in severity ,” the researchers noted .
“ Alongside data from other emerging treatments , ibrutinib might contribute to a reassessment of the role and timing of stem cell transplantation by changing the choice and sequence of treatments used for the management of highrisk CLL ,” Dr . O ’ Brien and authors concluded . “ These data mark an era of targeted therapeutics that is changing historical treatment algorithms for patients with del17p CLL or SLL , the most difficult subset of patients to treat .”
The study is limited by its singlearm , non-randomized design , and limited follow-up to determine the median PFS and OS .
REFERENCE
O ’ Brien S , Jones JA , Coutre SE , et al . Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion ( RESONATE-17 ): a phase 2 , open-label , multicenter study . Lancet Oncol . 2016 ; 17:1409-18 .
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