CLINICAL NEWS and 1 percent had high-risk MDS . Induction ( treatment cycles 1-2 ) consisted of cytarabine , daunorubicin , and etoposide ( ADE ); daunorubicin and cytarabine ( DA ); or fludarabine , high-dose cytarabine , granulocyte colony-stimulating factor , and idarubicin ( FLAG-Ida ) with or without gemtuzumab ozogamicin . Consolidation therapy ( treatment cycles 3-4 ) included cytarabine 1.5 g / m 2 or 3 g / m 2 or MACE / MidAC ( mitoxantrone and cytarabine ).
Brief Summary ( cont ’ d )
Table 5 : Thrombocytopenia and Neutropenia ( pooled adverse event and laboratory data )
NINLARO + Lenalidomide and Dexamethasone N = 360
Lestaurtinib was administered 48 hours after completion of cycle 1 of induction therapy , for a maximum of four 28-day cycles . The initial dose was 80 mg administered orally twice daily with 12 hours between doses . If that was well tolerated , a maximum dose of 100 mg administered orally twice daily was permitted after cycle 1 .
As of March 1 , 2015 , the median follow-up was 50.5 months ( range = 1.3-97 months ). Patients received a median of three
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 . cycles of lestaurtinib ( range = 0-4 cycles ).
The five-year overall survival ( OS ) and five-year relapse-free survival ( RFS ) rates , the study ’ s co-primary endpoints , were similar in the lestaurtinib and the control groups :
• 5-year OS : 46 % vs . 45 % ( hazard ratio [ HR ] = 0.90 ; 95 % CI 0.70-1.15 ; p = 0.3 )
• 5-year RFS : 40 % vs . 36 ( HR = 0.88 ; 95 % CI 0.69-1.12 ; p = 0.3 )
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 )
“ Only marginal differences in toxicity were seen between the lestaurtinib and control arms ,” the authors reported . Patients treated with lestaurtinib were more likely to require antibiotics , and there was a slightly higher need for supportive care , which was associated with a two-day increase in median time to platelet recovery ( p = 0.01 ). There also was no significant difference in 30-day or 60-day mortality between the treatment arms .
In an analysis of FLT3 inhibition in 83 patients , those who received lestaurtinib experienced greater degrees of FLT3 inhibition : 82 percent ( n = 68 / 83 ) achieved at least one FLT3 plasma inhibitory activity ( PIA ) measurement > 85 %, with 64 percent ( n = 53 / 83 ) showing > 85 percent inhibition at all time points .
Patients who experienced FLT3 inhibition had lower rates of relapse ( 43 % vs . 68 %; HR = 0.44 ; 95 % CI 0.23- 0.86 ; p = 0.02 ), leading to significantly better OS ( 60 % vs . 33 %; HR = 0.50 ; 95 % CI 0.26-0.97 ; p = 0.04 ).
“ There was a clear relationship among patients who demonstrated sustained inhibition of FLT3 and significant improvement in OS and reduction in relapse frequency ,” Dr . Knapper told ASH Clinical News . He noted that the fact that lestaurtinib failed to add any significant benefit over standard chemotherapy is a limitation of the study ’ s findings , but added that “ these results reinforce FLT3 as a therapeutic target , because they show that if sustained inhibition is achieved , there is a significant benefit . These data provide a lot of encouragement for the FLT3 studies going forward with a better compound and more favorable pharmacokinetics .”
ASH Clinical News spoke with study co-author Mark Levis , MD , PhD , about placing the results of this study in the context of the results from the RATIFY trial , which found that the addition of the FLT3 inhibitor midostaurin to standard chemotherapy improved five-year OS ( 51 % vs . 43 %; p = 0.007 ) in a similar patient population . “ Lestaurtinib , like midostaurin , is a pan-kinase inhibitor , but one that is even less selective , or more pan-inhibitory ,” Dr . Levis explained . “ When we studied lestaurtinib in the relapsed setting , the correlative data indicated that whatever benefit the drug provided was offset by the toxicities it created . I think the field is moving in the direction of more specific , more potent FLT3 inhibitors , which will probably be better tolerated as well .” ●
REFERENCE
Knapper S , Russell N , Gilkes A , et al . A randomised assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy from FLT3-mutated acute myeloid leukemia . Blood . 2016 November 21 . [ Epub ahead of print ]
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