CLINICAL NEWS lymphoma ( SLL ; n = 55 ; 26.2 %), treatmentnaïve CLL ( n = 18 ; 8.6 %), T-cell NHL ( n = 35 ; 16.7 %), and other ( n = 71 ; 33.8 %; the most common diagnoses in this cohort were aggressive NHL [ n = 26 ; 12.4 %], mantle cell lymphoma [ n = 10 ; 4.8 %], acute myeloid leukemia [ n = 6 ; 2.9 %], and myelodysplastic syndromes [ n = 6 ; 2.9 %]).
In the dose-escalation phase , 31 adult patients with advanced hematologic malignancies received duvelisib at eight doses
Immunogenicity All clinical trial subjects were monitored for neutralizing antibodies ( inhibitors ) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY , at defined intervals during the studies and at the completion visit .
Clinical trials ( Phases 1 through 3 ) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A ( Factor VIII < 1 %) with previous exposure to Factor VIII concentrates ≥50 EDs , and no history of inhibitors .
In the completed studies , no PTP developed neutralizing antibodies to Factor VIII . In an ongoing extension study , a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies . The Factor VIII recovery was 2.2 IU / dL per IU / kg , annualized bleeding rate ( ABR ) was zero , and no change in therapy was required .
In an actively enrolling clinical trial in PUPs , 6 of 14 treated subjects ( 42.9 % with a 95 % Confidence Interval of 17.7-71.1 %) developed an inhibitor . Of these , 3 subjects ( 21.4 %) had high titer inhibitors , and 3 subjects ( 21.4 %) had transient low titer inhibitors for which no change in therapy was required .
The detection of antibody formation is dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk . Animal reproduction studies have not been conducted using KOVALTRY . It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity . KOVALTRY should be given to a pregnant woman only if clearly needed . 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 .
8.2 Lactation Risk Summary There is no information regarding the presence of KOVALTRY in human milk , the effects on the breastfed infant , or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition .
( ranging from 8-100 mg ) in a standard 3 + 3 design . People in this cohort had disease that progressed following or was refractory to established therapy . Those with previous exposure to PI3K inhibitors or a diagnosis of overt leptomeningeal leukemia or central nervous system lymphoma were excluded .
In the dose-expansion cohort ( n = 179 ), enrollment criteria were similar , except patients who previously received
PI3K inhibitors and those with inadequate bone marrow function were eligible for inclusion .
The median duration of duvelisib treatment was 16 weeks ( range = 0.3-166.6 weeks ) across all dosing groups . Twenty patients with relapsed / refractory CLL / SLL ( 36.4 %) and 12 patients with treatmentnaïve CLL ( 66.7 %) remained on duvelisib for more than one year ( or at least 12 cycles of 28 days each ).
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8.4 Pediatric Use Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs . Body weight adjusted clearance of Factor VIII in children ≤12 years of age is higher than in adults and adolescents . Consider higher or more frequent dosing in children to account for this difference in clearance [ see Clinical Pharmacology ( 12.3 )].
8.5 Geriatric Use Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients . However , clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients . As with any patient receiving recombinant Factor VIII , dose selection for an elderly patient should be individualized .
17 PATIENT COUNSELING INFORMATION
• Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ).
• Hypersensitivity reactions are possible with KOVALTRY [ see Warnings and Precautions ( 5.1 )]. Warn patients of the early signs of hypersensitivity reactions ( including tightness of the chest or throat , dizziness , mild hypotension and nausea during infusion ) which can progress to anaphylaxis . Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen .
• Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [ see Warnings and Precautions ( 5.2 )]. Advise patients to contact their physician or treatment center for further treatment and / or assessment , if they experience a lack of clinical response to Factor VIII replacement therapy , as this may be a manifestation of an inhibitor .
• Advise patients to discard all equipment , including any unused product , in an appropriate container .
• Advise patients to consult with their healthcare provider prior to travel . Advise patients to bring an adequate supply of KOVALTRY while traveling based on their current regimen of treatment .
Resources at Bayer available to the patient : For Adverse Reaction Reporting , contact Bayer Medical Communications 1-888-84-BAYER ( 1-888-842-2937 )
To receive more product information , contact KOVALTRY Customer Service 1-888-606-3780
Bayer Reimbursement HELPline 1-800-288-8374 For more information , visit www . KOVALTRY-us . com
Bayer HealthCare LLC Whippany , NJ 07981 USA
U . S . License No . 8 6907500BS
In the dose-escalation phase , four patients experienced dose-limiting toxicities , including grade 4 neutropenia at 15 mg , grade 3 cellulitis at 75 mg , and grade 3 alanine transaminase ( ALT ) and aspartate transaminase ( AST ) and rash at 100 mg . Based on these results , the researchers determined the maximum tolerated dose of duvelisib to be 75 mg .
Pharmacokinetic analyses included
207 patients from both cohorts . The researchers found that a single dose of duvelisib was rapidly absorbed , reaching peak concentration within two hours . A single dose also induced rapid reductions in phospho-AKT ( p-AKT ), “ a key mediator of PI3K signaling ,” that were sustained at 24 hours in most patient samples , the authors wrote .
“ [ The findings ] support continued development as a potential contributor to the lymphoma and leukemia treatment paradigm .”
— IAN W . FLINN , MD , PhD
Peak p-AKT and Ki-67 effects were achieved at the duvelisib 25 mg dose , prompting investigators to select this dose for future evaluation in phase II and III studies .
The most common any-grade hematologic adverse events ( AEs ) associated with duvelisib were neutropenia ( n = 81 ; 38.6 %), anemia ( n = 52 ; 24.8 %), and thrombocytopenia ( n = 40 ; 23.3 %). The most common any-grade nonhematologic AEs were diarrhea ( n = 88 ; 41.9 %), fatigue ( n = 85 ; 40.5 %), and pyrexia ( n = 74 ; 35.2 %). The researchers also observed ALT ( n = 81 ; 38.6 %) and AST ( n = 79 ; 37.6 %) elevations early in treatment , with a median time of onset of 1.2 months ( range not provided ).
“ Not surprisingly , given the patient population , infections of all grades were common , reported in 128 ( 61 %) patients ,” the investigators observed , with the most frequent being upper respiratory tract infections ( n = 34 ; 16.2 %). Based on safety findings , the
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