ADCETRIS

Brentuximab vedotin, also known as Adcetris®, is an antibody-drug conjugate that combines an anti-CD30 antibody with the drug monomethyl auristatin E (MMAE).

It is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma.

Brentuximab vedotin was initially approved in 2011.

In January 2012, the drug label was revised with a boxed warning of a condition known as progressive multifocal leukoencephalopathy and death due to opportunistic JC virus infection post-treatment.

Adcetris has also been previously approved by the FDA to treat Hodgkin's lymphoma after relapse, Hodgkin's lymphoma after stem cell transplantation when a patient has a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after the failure of other treatment regimens, and primary cutaneous ALCL after failure of other treatment regimens.

Lymphoma is a malignancy that begins in the lymphatic system, which helps to combat infection and disease.

Lymphoma may begin anywhere in the body and can spread to nearby lymph nodes.

The two main types of lymphoma are Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma.

Most individuals with

Hodgkin's lymphoma have the classical type.

In this type of lymphoma, large, abnormal lymphocytes (a type of white blood cell) are found in the lymph nodes called Reed-Sternberg cells.

With early diagnosis and intervention, patients with Hodgkin lymphoma normally experience long-term remission.

ECHELON-1 study results demonstrated superior efficacy of the drug combined with a chemotherapy regimen compared to the previous standard of care.

Importantly, bleomycin.

• a highly toxic agent.

• was completely removed from the regimen.

This demonstrates meaningful progress in treatment for patients affected by this disease.

Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or Intravenous classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine.

It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression.

Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT.

Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone.

It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen.

Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic therapy.

Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation.

Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma.

March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/Intravenous disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens.

ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP.

BEACOPP leads to a greater progression-free survival but no difference in overall survival.

Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules.

Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells.

The effect of

Brentuximab vedotin (1.8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies.

Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels.

Smaller increases in the mean

QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm.

Tumor necrosis factor receptor superfamily member 8 Binder Antibody Regulator.

Steady-state of the

ADC is achieved within 21 days with every 3-week dosing of Adcetris.

Minimal to no accumulation of

ADC is observed with multiple doses at the every 3-week schedule.

The time to maximum concentration for

MMAE ranges from approximately 1-3 days.

Similar to the

ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris.

MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses.

The AUC of

MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function.

is unlikely to displace or to be displaced by highly protein-bound drugs.

In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp.

Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized.

In vitro data indicate that the

MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5.

In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms.

MMAE did not induce any major

CYP450 enzymes in primary cultures of human hepatocytes.

Hover over products below to view reaction partners Brentuximab vedotin Monomethyl Auristatin E (MMAE).

This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC).

An excretion study was done in patients receiving a dose of 1.8 mg/kg of Adcetris.

About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame.

Of the recovered

MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug.

The liver is the primary route of clearance for MMAE.

The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe 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.

It is recommended to avoid use in patients with severe renal impairment (CrCl <30 mL/min).

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The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease).

Symptoms of this condition begin insidiously and usually worsen progressively.

The symptoms vary depending on which region of the brain is infected.

In about two out of three patients, mental function deteriorates rapidly, leading to dementia.

Speaking and walking may become increasingly difficult.

Vision may be impaired, and total blindness may occur.

Rarely, headaches and seizures can occur, mainly in immunocompromised patients.

The most serious sequela of this condition is death.

Common adverse effects of

Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever.

In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever).

Preventive treatment with

G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or Intravenous cHL.

Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal.

Serious risks of

Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications.

Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris.

MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.

This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug.

Fertility studies with Brentuximab vedotin or

MMAE have not been conducted.

Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility.

In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed.

Effects in animals were seen mostly at and 10 mg/kg doses of brentuximab vedotin.

These dosages are approximately and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight.

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

Concomitant use with bleomycin due to pulmonary toxicity.

• Administer only as an intravenous infusion over 30 minutes.

• The recommended dosage as monotherapy for adult patients is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks.

• The recommended dosage in combination with chemotherapy for adult patients with previously untreated Stage III or IV cHL is 1.2 mg/kg up to a maximum of 120 mg every 2 weeks for a maximum of 12 doses.

• The recommended dosage in combination with chemotherapy for pediatric patients 2 years and older with previously untreated high risk cHL is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks for a maximum of 5 doses.

• The recommended dosage in combination with chemotherapy for adult patients with previously untreated PTCL is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks for to 8 doses.

• The recommended dosage in combination with lenalidomide and a rituximab product for adult patients with relapsed or refractory LBCL is 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

• Avoid use in patients with severe renal impairment.

• Reduce dose in patients with mild hepatic impairment; avoid use in patients with moderate or severe hepatic impairment. 2.1 Recommended Dosage The recommended ADCETRIS dosage is provided in Table 1.

ADCETRIS as a 30-minute intravenous infusion.

For recommended dosage for patients with renal or hepatic impairment, see Dosage and Administration.

For dosing instructions of combination agents administered with ADCETRIS, see Clinical Studies (14.1, 14.2, and 14.5 ) and the manufacturer’s prescribing information.

Table 1: Recommended ADCETRIS Dosage Indication Recommended Dose The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Frequency and Duration Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma 1.2 mg/kg up to a maximum of 120 mg in combination with chemotherapy Administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity Pediatric patients with previously untreated high risk classical Hodgkin lymphoma 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy Administer every 3 weeks with each cycle of chemotherapy for a maximum of 5 doses Adult patients with classical Hodgkin lymphoma consolidation 1.8 mg/kg up to a maximum of 180 mg Initiate ADCETRIS treatment within 4‑6 weeks post-auto-HSCT or upon recovery from auto-HSCT Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Adult patients with relapsed classical Hodgkin lymphoma 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until disease progression or unacceptable toxicity Adult patients with previously untreated systemic ALCL or other CD30-expressing peripheral T-cell lymphomas 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy Administer every 3 weeks with each cycle of chemotherapy for to 8 doses Adult patients with relapsed Systemic ALCL 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until disease progression or unacceptable toxicity Adult patients with relapsed primary cutaneous ALCL or CD30-expressing mycosis fungoides 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Adult patients with relapsed or refractory LBCL 1.2 mg/kg up to a maximum of 120 mg in combination with lenalidomide and rituximab Starting with cycle 2, rituximab intravenous treatment could be substituted with rituximab and hyaluronidase human via subcutaneous injection every 3 weeks.

Administer every 3 weeks until disease progression, or unacceptable toxicity 2.2 Recommended Dosage in Patients with Renal Impairment No dosage adjustment is required for mild renal impairment (CrCL greater than 50‑80 mL/min) and moderate renal impairment (CrCL 30-50 mL/min).

Avoid use in patients with severe (CrCL less than 30 mL/min) renal impairment. 2.3 Recommended Dosage in Patients with Hepatic Impairment Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma Reduce the dosage of ADCETRIS to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks for patients with mild hepatic impairment (Child-Pugh A).

Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.

Adult patients with relapsed or refractory LBCL Reduce the dosage of ADCETRIS to 0.9 mg/kg up to a maximum of 90 mg every 3 weeks for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate transaminase [AST] > ULN, or total bilirubin >1 to 1.5 × ULN and any AST).

Avoid use in patients with moderate and severe hepatic impairment (total bilirubin >1.5 × ULN) .

Hepatic impairment is defined per the National Cancer Institute Organ Dysfunction Working Group.

All other indications Reduce the dosage of ADCETRIS to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks for patients with mild hepatic impairment (Child-Pugh A).

Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment. 2.4 Recommended Prophylactic Medications In adult patients with previously untreated Stage III or IV cHL who are treated with ADCETRIS + doxorubicin, vinblastine, and dacarbazine (AVD), administer G‑CSF beginning with Cycle 1.

In pediatric patients with previously untreated high risk cHL who are treated with ADCETRIS + doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (AVEPC), administer G-CSF beginning with Cycle 1.

In adult patients with previously untreated PTCL who are treated with ADCETRIS + cyclophosphamide, doxorubicin, and prednisone (CHP), administer G-CSF beginning with Cycle 1.

In adult patients with relapsed or refractory LBCL who are treated with ADCETRIS + lenalidomide + rituximab, administer G-CSF beginning with Cycle 1. 2.5 Dosage Modifications for Adverse Reactions Table 2: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Adult Patients Recommended ADCETRIS Dosage from Table The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Monotherapy or Combination Therapy Severity Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.

Neuropathy 1.2 mg/kg up to a maximum of 120 mg every 2 weeks In combination with chemotherapy Grade 2 Reduce dose to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks.

Grade 3 Hold ADCETRIS dosing until improvement to Grade 2 or lower.

Restart at 0.9 mg/kg up to a maximum of 90 mg every 2 weeks.

Consider modifying the dose of other neurotoxic chemotherapy agents.

Grade 4 Discontinue dosing. 1.2 mg/kg up to a maximum of 120 mg every 3 weeks In combination with lenalidomide and rituximab Grade 2 Sensory neuropathy: If resolves to Grade 1 or lower before the next scheduled dose, resume at the same dose level.

If Grade 2 persists at the next scheduled dose, reduce one dose level.

Motor neuropathy

Reduce dosage to 0.9 mg/kg up to a maximum of 90 mg every 3 weeks.

Grade 3 Sensory neuropathy: Hold ADCETRIS dosing until improvement to Grade 2 or lower, then restart treatment at a reduced dosage of 0.9 mg/kg up to a maximum of 90 mg every 3 weeks.

Discontinue dosing.

Grade 4 Discontinue dosing. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks As monotherapy New or worsening Grade 2 or 3 Hold dosing until improvement to baseline or Grade 1.

Restart at 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade 4 Discontinue dosing.

In combination with chemotherapy

Grade 2 Sensory neuropathy: Continue treatment at same dose.

Reduce dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade 3 Sensory neuropathy: Reduce dose to 1.2 mg/kg, up to a maximum of 120 mg every 3 weeks.

Neutropenia 1.2 mg/kg up to a maximum of 120 mg every 2 weeks In combination with chemotherapy Grade 3 or 4 Administer G‑CSF prophylaxis for subsequent cycles for patients not receiving primary G‑CSF prophylaxis. 1.2 mg/kg up to a maximum of 120 mg every 3 weeks In combination with lenalidomide and rituximab Grade 3 or 4 Hold dosing until improvement to baseline or Grade 2 or lower.

Reduce/discontinue lenalidomide dose per prescribing information.

G-CSF prophylaxis for subsequent cycles for patients not receiving primary G-CSF prophylaxis. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks In combination with chemotherapy Grade 3 or 4 Administer G-CSF prophylaxis in subsequent cycles for patients not receiving primary G-CSF prophylaxis. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks As monotherapy Grade 3 or 4 Hold dosing until improvement to baseline or Grade 2 or lower.

G-CSF prophylaxis for subsequent cycles.

Grade 4 despite G‑CSF prophylaxis Consider discontinuation or dose reduction to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Table 3: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Pediatric Patients Recommended ADCETRIS Dosage from Table The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Severity Dosage Modification Peripheral Neuropathy Peripheral neuropathy was assessed using the Balis scale. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Grade 2 Reduce dose of vincristine per prescribing information.

Continue dosing with

If neuropathy improves to

Grade ≤1 by day of next cycle, then resume vincristine at full dose.

Grade 3 Discontinue vincristine.

Hold ADCETRIS dosing until improvement to ≤ Grade 2 then restart at 1.2 mg/kg up to a maximum of 120 mg. Second Occurrence: Hold until improvement to ≤ Grade 2 then restart at 0.8 mg/kg up to a maximum of 80 mg. Third Occurrence: Discontinue ADCETRIS.

Grade 4 Discontinue ADCETRIS and vincristine.

Neutropenia 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Grade 3 or 4 Reduce dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks in patients who are unable to start a cycle >5 weeks after the start of the previous cycle (>2-week delay) due to neutropenia. 2.6 Instructions for Preparation and Administration Administration.

• Administer ADCETRIS as an intravenous infusion only.

• Do not mix ADCETRIS with, or administer as an infusion with, other medicinal products.

• Follow procedures for proper handling and disposal of hazardous drugs 1.

• Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.

• Determine the number of 50 mg vials needed based on the patient’s weight and the prescribed dose.

• Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection to yield a single-dose solution containing 5 mg/mL brentuximab vedotin.

• Direct the stream toward the wall of vial and not directly at the cake or powder.

• Gently swirl the vial to aid dissolution.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.

• Following reconstitution, dilute immediately into an infusion bag.

If not diluted immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) and use within 24 hours of reconstitution.

• Discard any unused portion left in the vial.

• Calculate the required volume of 5 mg/mL reconstituted ADCETRIS solution needed.

• Withdraw this amoun.

• NDC, 50 mg brentuximab vedotin Storage Store vial refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

ADCETRIS is a hazardous product.

Follow special handling and disposal procedures 1.

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.

The available data from case reports on ADCETRIS use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

Advise a pregnant woman of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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.

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 and 13).

Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 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 cHL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

The safety and effectiveness of

ADCETRIS have been established in pediatric patients age 2 years and older with previously untreated high risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

ADCETRIS have not been established for all other indications.

Untreated, High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Doxorubicin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide The safety and effectiveness of ADCETRIS have been established in pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide chemotherapy.

Use of ADCETRIS for this indication is supported by evidence from Study 7: AHOD1331, a randomized study which included pediatric patients with previously untreated high risk cHL, including patients in the following age groups: 9 patients to less than 6 years of age, 81 patients to less than 12 years of age, and 345 patients to less than 17 years of age.

The safety and efficacy of

ADCETRIS have not been established for this indication in patients younger than 2 years.

Previously Untreated High Risk Classical Hodgkin

Lymphoma (cHL) in Combination with Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Prednisone, and Dacarbazine The safety and effectiveness of ADCETRIS in combination with etoposide (E), prednisone (P), and doxorubicin (A)/cyclophosphamide (C), prednisone (P), and dacarbazine (Dac) (AEPA/CAPDac) were assessed but have not been established based on a single arm, open-label trial (NCT01920932) in 77 patients, which included 48 pediatric patients age to less than with previously untreated high risk (IIB, IIIB, IVA, or IVB) cHL.

No new safety signals were identified in this study.

HL (cHL) ADCETRIS in Combination with Gemcitabine The safety and effectiveness of ADCETRIS in combination with gemcitabine were assessed but have not been established based on a study (NCT01780662) in 45 patients, which included 18 pediatric patients age to less than with relapsed or refractory cHL.

ADCETRIS Monotherapy The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 15 pediatric patients age to less than with relapsed or refractory cHL.

ALCL (sALCL) ADCETRIS monotherapy The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 16 pediatric patients age to less than with sALCL.

ALK+ ALCL The safety and effectiveness of ADCETRIS in combination with alternating chemotherapy Courses A (dexamethasone, ifosfamide, methotrexate, etoposide, cytarabine) and B (dexamethasone, methotrexate, cyclophosphamide, doxorubicin) administered every 21 days for a total of 6 cycles was assessed but have not been established based on a study (NCT01979536) in 67 patients, which included 61 pediatric patients age to less than 17 years with newly diagnosed ALK+ ALCL.

In the clinical trial of ADCETRIS in combination with AVD for patients with previously untreated Stage III or IV cHL (Study 5: ECHELON-1), 9% of ADCETRIS + AVD-treated patients were age and older.

Older age was a risk factor for febrile neutropenia, occurring in 39% of patients who were age and older versus 17% of patients less than age 65, who received ADCETRIS + AVD.

ECHELON-1 trial did not contain sufficient information on patients age and older to determine whether they respond differently from younger patients.

In the clinical trial of ADCETRIS in combination with CHP for patients with previously untreated, CD30-expressing PTCL (Study 6: ECHELON-2), 31% of ADCETRIS + CHP-treated patients were age and older.

Among older patients, 74% had adverse reactions ≥ Grade and 49% had serious adverse reactions.

Among patients younger than age 65, 62% had adverse reactions ≥ Grade and 33% had serious adverse reactions.

Older age was a risk factor for febrile neutropenia, occurring in 29% of patients who were age and older versus 14% of patients less than age 65.

Other clinical trials of

ADCETRIS in cHL (Study 1; Study 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients who were age and older to determine whether they respond differently from younger patients.

In the clinical trial of ADCETRIS in pcALCL or CD30-expressing MF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were age and older.

No meaningful differences in safety or efficacy were observed between these patients and younger patients.

In the clinical trial of ADCETRIS in relapsed or refractory LBCL (Study 8: ECHELON-3) , 79 (71%) of ADCETRIS-treated patients were age and older.