CLINICAL NEWS combination regimen , while there were no significant differences between treatment groups for some of the secondary endpoints , including overall response at the end of the induction phase ( 69 % in the combination group vs . 63 % in the monotherapy group ; p = 0.31 ), best overall response ( 79 % vs . 77 %; p = 0.74 ), and overall survival ( 18 % vs . 20 %; p = 0.4 ).
Nearly all patients ( ≥98 %) reported
Brief Summary ( cont ’ d )
Table 5 : Thrombocytopenia and Neutropenia ( pooled adverse event and laboratory data )
NINLARO + Lenalidomide and Dexamethasone N = 360
Placebo + Lenalidomide and Dexamethasone N = 360
N (%) N (%)
Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 281 ( 78 ) 93 ( 26 ) 196 ( 54 ) 39 ( 11 ) Neutropenia 240 ( 67 ) 93 ( 26 ) 239 ( 66 ) 107 ( 30 )
Eye Disorders
Eye disorders were reported with many different preferred terms but in aggregate , the frequency was 26 % in patients in the NINLARO regimen and 16 % of patients in the placebo regimen . The most common adverse reactions were blurred vision ( 6 % in the NINLARO regimen and 3 % in the placebo regimen ), dry eye ( 5 % in the NINLARO regimen and 1 % in the placebo regimen ), and conjunctivitis ( 6 % in the NINLARO regimen and 1 % in the placebo regimen ). Grade 3 adverse reactions were reported in 2 % of patients in the NINLARO regimen and 1 % in the placebo regimen .
The following serious adverse reactions have each been reported at a frequency of < 1 %: acute febrile neutrophilic dermatosis ( Sweet ’ s syndrome ), Stevens-Johnson syndrome , transverse myelitis , posterior reversible encephalopathy syndrome , tumor lysis syndrome , and thrombotic thrombocytopenic purpura .
7 DRUG INTERACTIONS
7.1 Strong CYP3A Inducers : Avoid concomitant administration of NINLARO with strong CYP3A inducers ( such as rifampin , phenytoin , carbamazepine , and St . John ’ s Wort )
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy : Women should avoid becoming pregnant while being treated with NINLARO .
Risk Summary : NINLARO can cause fetal harm when administered to a pregnant woman . There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus . Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose . Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively . Animal Data : In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations / abnormalities ( caudal vertebrae , number of lumbar vertebrae , and full supernumerary ribs ) at doses that were also maternally toxic ( ≥ 0.3 mg / kg ). Exposures in the rabbit at 0.3 mg / kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg . In a rat dose range-finding embryo-fetal development study , at doses that were maternally toxic , there were decreases in fetal weights , a trend towards decreased fetal viability , and increased post-implantation losses at 0.6 mg / kg . Exposures in rats at the dose of 0.6 mg / kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg .
8.2 Lactation : It is not known whether NINLARO or its metabolites are present in human milk . Many drugs are present in human milk and as a result , there could be a potential for adverse events in nursing infants . Advise women to discontinue nursing .
8.3 Females and Males of Reproductive Potential : Contraception - Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment . Infertility - Fertility studies were not conducted with NINLARO ; however there were no effects on reproductive organs in either males or females in nonclinical studies in rats and dogs
8.4 Pediatric Use : Safety and effectiveness have not been established in pediatric patients .
8.5 Geriatric Use : Of the total number of subjects in clinical studies of NINLARO , 55 % were 65 and over , while 17 % were 75 and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
8.6 Hepatic Impairment : In patients with moderate or severe hepatic impairment , the mean AUC increased by 20 % when compared to patients with normal hepatic function . Reduce the starting dose of NINLARO in patients with moderate or severe hepatic impairment . at least one adverse event ( AE ), with grade 3-5 AEs reported in 68 percent of patients in the combination group ( n = 132 / 195 ) and 62 percent in the monotherapy group ( n = 123 / 198 ). The most frequent all-cause grade ≥3 AEs included neutropenia ( 33 % vs . 26 %), thrombocytopenia ( 11 % vs . 16 %), anemia ( 8 % vs . 10 %), and infusion-related reactions ( IRRs ; 11 % vs . 6 %).
8.7 Renal Impairment : In patients with severe renal impairment or ESRD requiring dialysis , the mean AUC increased by 39 % when compared to patients with normal renal function . Reduce the starting dose of NINLARO in patients with severe renal impairment or ESRD requiring dialysis . NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis .
10 OVERDOSAGE : There is no known specific antidote for NINLARO overdose . In the event of an overdose , monitor the patient for adverse reactions and provide appropriate supportive care .
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling ( Patient Information ).
Dosing Instructions
• Instruct patients to take NINLARO exactly as prescribed .
• Advise patients to take NINLARO once a week on the same day and at approximately the same time for the first three weeks of a four week cycle .
• Advise patients to take NINLARO at least one hour before or at least two hours after food .
• Advise patients that NINLARO and dexamethasone should not be taken at the same time , because dexamethasone should be taken with food and NINLARO should not be taken with food .
• Advise patients to swallow the capsule whole with water . The capsule should not be crushed , chewed or opened .
• Advise patients that direct contact with the capsule contents should be avoided . In case of capsule breakage , avoid direct contact of capsule contents with the skin or eyes . If contact occurs with the skin , wash thoroughly with soap and water . If contact occurs with the eyes , flush thoroughly with water .
• If a patient misses a dose , advise them to take the missed dose as long as the next scheduled dose is ≥ 72 hours away . Advise patients not to take a missed dose if it is within 72 hours of their next scheduled dose .
• If a patient vomits after taking a dose , advise them not to repeat the dose but resume dosing at the time of the next scheduled dose .
• Advise patients to store capsules in original packaging , and not to remove the capsule from the packaging until just prior to taking NINLARO .
Thrombocytopenia : Advise patients that they may experience low platelet counts ( thrombocytopenia ). Signs of thrombocytopenia may include bleeding and easy bruising .
Gastrointestinal Toxicities : Advise patients they may experience diarrhea , constipation , nausea and vomiting and to contact their physician if these adverse reactions persist .
Peripheral Neuropathy : Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling , numbness , pain , a burning feeling in the feet or hands , or weakness in the arms or legs .
Peripheral Edema : Advise patients to contact their physicians if they experience unusual swelling of their extremities or weight gain due to swelling .
Cutaneous Reactions : Advise patients to contact their physicians if they experience new or worsening rash .
Hepatotoxicity : Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain .
Pregnancy : Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO and for 90 days following the final dose . Advise patients to contact their physicians immediately if they or their female partner become pregnant during treatment or within 90 days of the final dose .
Concomitant Medications : Advise patients to speak with their physicians about any other medication they are currently taking and before starting any new medications .
Please see full Prescribing Information for NINLARO at NINLARO-hcp . com .
NINLARO is a registered trademark of Millennium Pharmaceuticals , Inc . Millennium Pharmaceuticals , Inc . is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited .
© 2016 Millennium Pharmaceuticals , Inc . 20160209 v2 USO / IXA / 15 / 0123 ( 2 )
Although more patients in the combination group had a grade 3 or 4 IRR , these were mainly managed supportively , and led to treatment withdrawal in only four patients , Dr . Sehn and colleagues reported . Overall , “ obinutuzumab plus bendamustine was well tolerated with a similar safety profile to bendamustine monotherapy , despite treatment and adverse event reporting periods being much longer in the combination group .”
Deaths occurred in 18 percent of those in the combination group ( n = 34 ) and 21 percent of the monotherapy group ( n = 41 ). In the combination group , 22 deaths were related to disease progression ( 65 %), compared with 29 patients in the bendamustine group ( 71 %). AE-related deaths were similar in the two groups ( n = 12 ; 6 % for each ). This study was designed to assess PFS benefit after induction and maintenance treatment as a whole , meaning that “ the relative contribution of each treatment phase is difficult to assess , which is a limitation of this study ,” the authors concluded . Future studies , they suggested , could include a second control group treated with obinutuzumab plus bendamustine induction only and no maintenance therapy .
REFERENCE
Sehn LH , Chua N , Mayer J , et al . Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma ( GADOLIN ): A randomised , controlled , open-label , multicenter , phase 3 trial . J Clin Oncol . 2016 ; 17:1081-93 .
Nivolumab Safe and Effective for Treatment of Various Subtypes of Non- Hodgkin Lymphoma
Nivolumab , a monoclonal antibody that targets programmed death-1 ( PD-1 ) receptors on T cells , has previously been shown to produce durable responses in patients with solid tumors , and recent results from a phase Ib study published in the Journal of Clinical Oncology show that the drug was well toler-
ASH Clinical News 47