ASH Clinical News November 2016 | Page 24

Pulling Back the Curtain

ADCETRIS ® ( brentuximab vedotin ) for injection , for intravenous use Brief Summary : see package insert for complete prescribing information

WARNING : PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ( PML ) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS .

INDICATIONS AND USAGE

ADCETRIS is a CD30-directed antibody-drug conjugate indicated for the treatment of patients with classical Hodgkin Lymphoma ( HL ) at high risk of relapse or progression as post-auto-HSCT consolidation .

DOSAGE AND ADMINISTRATION Dosage Recommendations Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks .

For classical HL post-auto-HSCT consolidation treatment , initiate ADCETRIS treatment within 4-6 weeks post-auto-HSCT or upon recovery from auto-HSCT . These patients should continue treatment until a maximum of 16 cycles , disease progression , or unacceptable toxicity .

The recommended dose is 1.8 mg / kg up to 180 mg . Reduce the dose in patients with mild hepatic impairment ( Child-Pugh A ) to 1.2 mg / kg up to 120 mg . Avoid use in patients with moderate ( Child-Pugh B ) or severe ( Child-Pugh C ) hepatic impairment or severe renal impairment ( CLcr < 30 mL / min ).

Dose Modification

Peripheral Neuropathy : For new or worsening Grade 2 or 3 neuropathy , dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg / kg . For Grade 4 peripheral neuropathy , ADCETRIS should be discontinued .

Neutropenia : The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower . Consider G-CSF prophylaxis for subsequent cycles in patients who experience Grade 3 or 4 neutropenia in the previous cycle . In patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis , consider discontinuation or dose reduction of ADCETRIS to 1.2 mg / kg .

CONTRAINDICATIONS

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity ( e . g ., interstitial infiltration and / or inflammation ).

WARNINGS AND PRECAUTIONS Peripheral Neuropathy ( PN )

ADCETRIS treatment causes a PN that is predominantly sensory . Cases of motor PN have also been reported . ADCETRIS-induced PN is cumulative . In the relapsed classical HL and sALCL clinical trials , 54 % of patients experienced any grade of neuropathy . Of these patients , 49 % had complete resolution , 31 % had partial improvement , and 20 % had no improvement . Of the patients who reported neuropathy , 51 % had residual neuropathy at the time of their last evaluation . Monitor patients for symptoms of neuropathy , such as hypoesthesia , hyperesthesia , paresthesia , discomfort , a burning sensation , neuropathic pain , or weakness . Patients experiencing new or worsening PN may require a delay , change in dose , or discontinuation of ADCETRIS .

Anaphylaxis and Infusion Reactions

Infusion-related reactions , including anaphylaxis , have occurred with ADCETRIS . Monitor patients during infusion . If anaphylaxis occurs , immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy . If an infusion-related reaction occurs , the infusion should be interrupted and appropriate medical management instituted . Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions . Premedication may include acetaminophen , an antihistamine , and a corticosteroid .

Hematologic Toxicities

Prolonged ( ≥1 week ) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS . Febrile neutropenia has been reported with treatment with ADCETRIS . Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia . Monitor patients for fever . If Grade 3 or 4 neutropenia develops , consider dose delays , reductions , discontinuation , or G-CSF prophylaxis with subsequent ADCETRIS doses .

Serious Infections and Opportunistic Infections

Serious infections and opportunistic infections such as pneumonia , bacteremia , and sepsis or septic shock ( including fatal outcomes ) have been reported in patients treated with ADCETRIS . Patients should be closely monitored during treatment for the emergence of possible bacterial , fungal or viral infections .

Tumor Lysis Syndrome

Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome . Monitor closely and take appropriate measures .

Increased Toxicity in the Presence of Severe Renal Impairment

The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function . Due to higher monomethyl auristatin E ( MMAE ) exposure , ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function . Avoid the use of ADCETRIS in patients with severe renal impairment [ creatinine clearance ( CLcr ) < 30 mL / min ].

Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment

The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function . Avoid the use of ADCETRIS in patients with moderate ( Child-Pugh B ) or severe ( Child-Pugh C ) hepatic impairment .

Hepatotoxicity

Serious cases of hepatotoxicity , including fatal outcomes , have occurred in patients receiving ADCETRIS . Cases were consistent with hepatocellular injury , including elevations of transaminases and / or bilirubin . Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge . Preexisting liver disease , elevated baseline liver enzymes , and concomitant medications may also increase the risk . Monitor liver enzymes and bilirubin . Patients experiencing new , worsening , or recurrent hepatotoxicity may require a delay , change in dose , or discontinuation of ADCETRIS .

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients . First onset of symptoms occurred at various times from initiation of ADCETRIS therapy , with some cases occurring within 3 months of initial exposure . In addition to ADCETRIS therapy , other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression . Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities . Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed .

Pulmonary Toxicity

Events of noninfectious pulmonary toxicity including pneumonitis , interstitial lung disease , and acute respiratory distress syndrome ( ARDS ), some with fatal outcomes , have been reported . Monitor patients for signs and symptoms of pulmonary toxicity , including cough and dyspnea . In the event of new or worsening pulmonary symptoms , hold ADCETRIS dosing during evaluation and until symptomatic improvement .

Serious Dermatologic Reactions

Stevens-Johnson syndrome ( SJS ) and toxic epidermal necrosis ( TEN ), including fatal outcomes , have been reported with ADCETRIS . If SJS or TEN occurs , discontinue ADCETRIS and administer appropriate medical therapy .

Gastrointestinal ( GI ) Complications

Fatal and serious GI complications including perforation , hemorrhage , erosion , ulcer , intestinal obstruction , enterocolitis , neutropenic colitis , and ileus have been reported in ADCETRIS-treated patients . Lymphoma with preexisting GI involvement may increase the risk of perforation . In the event of new or worsening GI symptoms , perform a prompt diagnostic evaluation and treat appropriately .

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals , ADCETRIS can cause fetal harm when administered to a pregnant woman . There are no adequate and well-controlled studies of ADCETRIS in pregnant women . Brentuximab vedotin caused embryo-fetal toxicities , including significantly decreased embryo viability and fetal malformations , in animals at maternal exposures that were similar to the clinical dose of 1.8 mg / kg every 3 weeks . Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS . If ADCETRIS is used during pregnancy or if the patient becomes pregnant during ADCETRIS treatment , the patient should be apprised of the potential risk to the fetus .

ADVERSE REACTIONS Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT , the most common adverse reactions ( ≥20 %) in the ADCETRIS-treatment arm , regardless of causality , were neutropenia , peripheral sensory neuropathy , thrombocytopenia , anemia , upper respiratory tract infection , fatigue , peripheral motor neuropathy , nausea , cough , and diarrhea . The most common adverse reactions occurring in at least 10 % of patients , using the NCI CTC Version 4 , are shown in Table 1 .

Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation ( Study 3 )

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto- HSCT in a randomized , double-blind , placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg / kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles . Of the 329 enrolled patients , 327 ( 167 brentuximab vedotin , 160 placebo ) received at least one dose of study treatment . The median number of treatment cycles in each study arm was 15 ( range , 1 – 16 ) and 80 patients ( 48 %) in the ADCETRIS-treatment arm received 16 cycles .

Standard international guidelines were followed for infection prophylaxis for herpes simplex virus ( HSV ), varicella-zoster virus ( VZV ), and Pneumocystis jiroveci pneumonia ( PCP ) post-auto-HSCT . Overall , 312 patients ( 95 %) received HSV and VZV prophylaxis with a median duration of 11.1 months ( range , 0-20 ) and 319 patients ( 98 %) received PCP prophylaxis with a median duration of 6.5 months ( range , 0-20 ).

Table 1 : Most Commonly Reported ( ≥10 % in the ADCETRIS arm ) Adverse Reactions in Study 3

Adverse Reaction

Any Grade

ADCETRIS Total N = 167 % of patients

Grade 3

Grade 4

Any Grade

Placebo Total N = 160 % of patients

Grade 3

* Derived from laboratory values and adverse reaction data Additional Important Adverse Reactions Peripheral neuropathy

In Study 3 , 67 % of patients treated with ADCETRIS experienced any grade of neuropathy . The median time to first onset of any grade was 14 weeks ( range , 0.1 – 47 ), of Grade 2 was 27 weeks ( range , 0.4 – 52 ) and of Grade 3 was 34 weeks ( range , 7 – 106 ). The median time from onset to resolution or improvement of any grade was 23 weeks ( range , 0.1 – 138 ), of Grade 2 was 24 weeks ( range , 1 – 108 ) and of Grade 3 was 25 weeks ( range , 2 – 98 ). Of the patients who reported neuropathy , 59 % had complete resolution and 41 % had residual neuropathy ( 26 % partial improvement , 15 % no improvement ) at the time of their last evaluation .

Infusion reactions

Two cases of anaphylaxis were reported in the dose-finding trials . In Study 3 , infusion-related reactions were reported in 25 patients ( 15 %) in the ADCETRIS-treated arm and 3 patients ( 2 %) in the placebo arm . Grade 3 events were reported in 3 of the 25 ADCETRIS-treated patients who experienced infusion-related reactions . No Grade 4 infusion-related reactions were reported . The most common adverse reactions ( ≥2 %) associated with infusion-related reactions were nausea ( 4 %), chills ( 4 %), dyspnea ( 2 %), headache ( 2 %), pruritus ( 2 %), rash ( 2 %), back pain ( 2 %), and vomiting ( 2 %).

Pulmonary Toxicity

In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination regimen , the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported

Grade 4

Live : 10 ”

USP-BVP-2015-0161 ( 2 )_ ASH Clinical News Resize _ Journal _ Ad _ Label _ update _ D01 . indd 3 7 / 7 / 16 9:20 AM