CLINICAL NEWS
The one-year CRTI program begins with a week-long workshop offered to approximately 20 participants and led by approximately 20 established clinical researchers , as well as representatives from funding agencies such as the National Heart , Lung , and Blood Institute and the National Cancer Institute . The workshop includes presentations of each participant ’ s research project , lectures , and small-group sessions . After the workshop , small groups reconvene twice a year – at the ASH annual meeting in December and at the ASH headquarters in Washington , DC , in May .
Dr . King and authors conducted three sets of surveys among previous CRTI participants :
• Cross-sectional survey : This assessment was conducted in 2014 to capture the number of
with ABVD ( adriamycin , bleomycin , vinblastine , dacarbazine ). Patients typically reported cough and dyspnea . Interstitial infiltration and / or inflammation were observed on radiographs and computed tomographic imaging of the chest . Most patients responded to corticosteroids . The concomitant use of ADCETRIS with bleomycin is contraindicated .
Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS . In Study 3 , pulmonary toxicity was reported in 8 patients ( 5 %) in the ADCETRIS-treated arm and 5 patients ( 3 %) in the placebo arm . A causal association with single-agent ADCETRIS has not been established .
Serious adverse reactions
In Study 3 , serious adverse reactions , regardless of causality , were reported in 25 % of ADCETRIStreated patients . The most common serious adverse reactions were pneumonia ( 4 %), pyrexia ( 4 %), vomiting ( 3 %), nausea ( 2 %), hepatotoxicity ( 2 %) and peripheral sensory neuropathy ( 2 %).
Dose modifications
Adverse reactions that led to dose delays in more than 5 % of ADCETRIS-treated patients in Study 3 were neutropenia ( 22 %), peripheral sensory neuropathy ( 16 %), upper respiratory tract infection ( 6 %), and peripheral motor neuropathy ( 6 %).
Discontinuations
Adverse reactions led to treatment discontinuation in 32 % of ADCETRIS-treated patients in Study 3 . Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy ( 14 %), peripheral motor neuropathy ( 7 %), acute respiratory distress syndrome ( 1 %), paraesthesia ( 1 %) and vomiting ( 1 %).
Post Marketing Experience
The following adverse reactions have been identified during post-approval use of ADCETRIS . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
Blood and lymphatic system disorders : febrile neutropenia . Gastrointestinal disorders :
• Pancreatitis ( including fatal outcomes ). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain .
• Gastrointestinal complications ( including fatal outcomes ). Hepatobiliary disorders : hepatotoxicity . Infections : PML , serious infections and opportunistic infections . Metabolism and nutrition disorders : hyperglycemia .
Respiratory , thoracic and mediastinal disorders : noninfectious pulmonary toxicity including pneumonitis , interstitial lung disease , and ARDS ( some with fatal outcomes ).
Skin and subcutaneous tissue disorders : Toxic epidermal necrolysis , including fatal outcomes . Immunogenicity
Patients with classical HL and sALCL in Studies 1 and 2 were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay . Approximately 7 % of patients in these trials developed persistently positive antibodies ( positive test at more than 2 timepoints ) and 30 % developed transiently positive antibodies ( positive in 1 or 2 post-baseline timepoints ). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies . Two of the patients ( 1 %) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment . Overall , a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies .
A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies . Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies . The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known .
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity , assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading .
DRUG INTERACTIONS
In vitro data indicate that monomethyl auristatin E ( MMAE ) is a substrate and an inhibitor of CYP3A4 / 5 . In vitro data indicate that MMAE is also a substrate of the efflux transporter P-glycoprotein ( P-gp ).
Effect of Other Drugs on ADCETRIS
CYP3A4 Inhibitors / Inducers : MMAE is primarily metabolized by CYP3A . Co-administration of ADCETRIS with ketoconazole , a potent CYP3A4 inhibitor , increased exposure to MMAE by approximately 34 %. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions . Co-administration of ADCETRIS with rifampin , a potent CYP3A4 inducer , reduced exposure to MMAE by approximately 46 %.
P-gp Inhibitors : Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE . Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions .
Effect of ADCETRIS on Other Drugs
Co-administration of ADCETRIS did not affect exposure to midazolam , a CYP3A4 substrate . MMAE does not inhibit other CYP enzymes at relevant clinical concentrations . ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes .
USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug ’ s mechanism of action . In animal reproduction studies , administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg / kg every three weeks caused embryo-fetal toxicities including congenital malformations . Consider the benefits and risks of ADCETRIS and possible risks to the fetus when prescribing ADCETRIS to a pregnant woman .
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 .
Data Animal Data
In an embryo-fetal developmental study , pregnant rats received 2 intravenous doses of 0.3 , 1 , 3 , or 10 mg / kg brentuximab vedotin during the period of organogenesis ( once each on Pregnancy Days 6 and 13 ). Drug- induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg / kg of the drug and included increased early resorption ( ≥99 %), post-implantation loss ( ≥99 %), decreased numbers of live fetuses , and external malformations ( i . e ., umbilical hernias and malrotated hindlimbs ). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg / kg is approximately the same exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg / kg every three weeks .
Lactation
There is no information regarding the presence of brentuximab vedotin in human milk , the effects on the breastfed infant , or the effects on milk production . Because of the potential for serious adverse reactions in a breastfed infant from ADCETRIS , including cytopenias and neurologic or gastrointestinal toxicities , advise patients that breastfeeding is not recommended during ADCETRIS treatment . grants , publications , and research involvement a participant had within the previous year . Sixteen questions were focused on demographic characteristics and the participant ’ s perceived influence of CRTI participation on his or her career .
• Pre- and post-summer workshop analysis : Participants reported their confidence in research immediately
Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy . Contraception Females
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS . Advise females to immediately report pregnancy .
Males
ADCETRIS may damage spermatozoa and testicular tissue , resulting in possible genetic abnormalities . Males with female sexual partners of reproductive potential should use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS .
Infertility Males Based on findings in rats , male fertility may be compromised by treatment with ADCETRIS . Pediatric Use Safety and effectiveness of ADCETRIS have not been established in pediatric patients . Geriatric Use
Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients .
Renal Impairment Avoid the use of ADCETRIS in patients with severe renal impairment ( CLcr < 30 mL / min ).
The kidney is a route of excretion for monomethyl auristatin E ( MMAE ). The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg / kg of ADCETRIS to patients with mild ( CLcr > 50-80 mL / min ; n = 4 ), moderate ( CLcr 30-50 mL / min ; n = 3 ) and severe ( CLcr < 30 mL / min ; n = 3 ) renal impairment . In patients with severe renal impairment , the rate of Grade 3 or worse adverse reactions was 3 / 3 ( 100 %) compared to 3 / 8 ( 38 %) in patients with normal renal function . Additionally , the AUC of MMAE ( component of ADCETRIS ) was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function . Due to higher MMAE exposure , ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function .
Hepatic Impairment Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment .
The liver is a route of clearance for MMAE . The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg / kg of ADCETRIS to patients with mild ( Child-Pugh A ; n = 1 ), moderate ( Child-Pugh B ; n = 5 ) and severe ( Child-Pugh C ; n = 1 ) hepatic impairment . In patients with moderate and severe hepatic impairment , the rate of ≥Grade 3 adverse reactions was 6 / 6 ( 100 %) compared to 3 / 8 ( 38 %) in patients with normal hepatic function . Additionally , the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function .
OVERDOSAGE
There is no known antidote for overdosage of ADCETRIS . In case of overdosage , the patient should be closely monitored for adverse reactions , particularly neutropenia , and supportive treatment should be administered .
PATIENT COUNSELING INFORMATION
• Peripheral neuropathy
Advise patients that ADCETRIS can cause a peripheral neuropathy . They should be advised to report to their health care provider any numbness or tingling of the hands or feet or any muscle weakness .
• Fever / Neutropenia
Advise patients to contact their health care provider if a fever of 100.5 ° F or greater or other evidence of potential infection such as chills , cough , or pain on urination develops .
• Infusion reactions
Advise patients to contact their health care provider if they experience signs and symptoms of infusion reactions including fever , chills , rash , or breathing problems within 24 hours of infusion .
• Hepatotoxicity
Advise patients to report symptoms that may indicate liver injury , including fatigue , anorexia , right upper abdominal discomfort , dark urine , or jaundice .
• Progressive multifocal leukoencephalopathy
Instruct patients receiving ADCETRIS to immediately report if they have any of the following neurological , cognitive , or behavioral signs and symptoms or if anyone close to them notices these signs and symptoms :
• changes in mood or usual behavior
• confusion , thinking problems , loss of memory
• changes in vision , speech , or walking
• decreased strength or weakness on one side of the body
• Pulmonary Toxicity
Instruct patients to report symptoms that may indicate pulmonary toxicity , including cough or shortness of breath .
• Pancreatitis Advise patients to contact their health care provider if they develop severe abdominal pain .
• Gastrointestinal Complications
Advise patients to contact their health care provider if they develop severe abdominal pain , chills , fever , nausea , vomiting , or diarrhea .
• Females and Males of Reproductive Potential
ADCETRIS can cause fetal harm . Advise women receiving ADCETRIS to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS .
Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS .
Advise patients to report pregnancy immediately .
• Lactation Advise patients to avoid breastfeeding while receiving ADCETRIS .
ADCETRIS , Seattle Genetics are US registered trademarks of Seattle Genetics , Inc . © 2016 Seattle Genetics , Inc ., Bothell , WA 98021 All rights reserved . Printed in USA USP-BVP-2015-0127 ( 2 ) following the summer workshop . ( Only results from the 2014 to 2015 survey were included in this analysis because the questions were consistent , while the questions from the 2009 and 2015 surveys were not consistent .)
• Evaluation of mentorship program : Participants described the perceived outcome of mentor interaction in academic productivity or career opportunities . ( Results from the 2012 and 2013 surveys were evaluated because this survey was not distributed in 2014 or 2015 .)
Between 2005 and 2012 , the crosssectional survey was distributed to 160 participants ; 115 responded ( 72 % response rate ), but six responses did not include demographic data . Of the remaining 109 respondents , 42 percent had a focus on benign hematology , 65 percent treated adults , 48 percent were male , and 69 percent were white . At the time of program inclusion , 79 percent were fellows and 57 percent participated in 2009 or later .
“Our data further support the value of mentoring in training and retaining talented junior hematologists .”
— ALLISON A . KING , MD , MPH , PhD
After participants were given a series of statements about their experiences with CRTI , they were asked if they strongly disagreed , disagreed , agreed , or strongly agreed with the statements . Most respondents ( 63 %) strongly agreed that CRTI facilitated their career development as an independent researcher and , compared with the other 37 percent of respondents , those who strongly agreed were more likely to have had the following : at least one grant in the previous year ( 55 % vs . 33 %; p = 0.026 ), more published articles ( median = 3 vs . 2 ; p = 0.017 ), and a greater percent effort in research ( 50 % vs . 30 %; p < 0.0002 ). Dr . King and researchers found
ASH Clinical News 47