1 INDICATIONS AND USAGE

1.1 Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (cHL),

in Combination with Chemotherapy

ADCETRIS is indicated for the treatment of adult patients with previously untreated Stage III or IV cHL, in combination with doxorubicin, vinblastine, and dacarbazine.

1.2 Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL), in

Combination with Chemotherapy

ADCETRIS is indicated for the treatment of pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

1.3 Classical Hodgkin Lymphoma (cHL) Consolidation

ADCETRIS is indicated for the treatment of adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

1.4 Relapsed Classical Hodgkin Lymphoma (cHL)

ADCETRIS is indicated for the treatment of adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

1.5 Previously Untreated Systemic Anaplastic Large Cell Lymphoma (sALCL) or

Other CD30-Expressing Peripheral T-cell Lymphomas (PTCL), in Combination with Chemotherapy

ADCETRIS is indicated for the treatment of adult patients with previously untreated sALCL or other CD30-expressing PTCL, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.

1.6 Relapsed Systemic Anaplastic Large Cell Lymphoma (sALCL)

ADCETRIS is indicated for the treatment of adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

1.7 Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL) or

CD30-Expressing Mycosis Fungoides (MF)

ADCETRIS is indicated for the treatment of adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy.

4 CONTRAINDICATIONS

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative.

In studies of ADCETRIS as monotherapy, 62% of patients experienced any grade of peripheral neuropathy. The median time to onset was 3 months (range, 0–12). Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at their last evaluation. The median time from onset to resolution or improvement was 5 months (range, 0–45). Of the patients with ongoing neuropathy (38%), 71% had Grade 1, 24% had Grade 2, and 4% had Grade 3.

In ECHELON-1 (Study 5), 67% of patients treated with ADCETRIS + AVD experienced any grade of peripheral neuropathy. The median time to onset of any grade was 2 months (range, 0–7), of Grade 2 was 3 months (range, 0–6) and of Grade 3 was 4 months (range, <1–7). By the time of the primary analysis, 43% of affected patients had complete resolution, 24% had partial improvement, and 33% had no improvement at their last evaluation. The median time from onset to resolution or improvement of any grade was 2 months (range, 0–32).

At the updated analysis of ECHELON-1, 72% of the patients who experienced peripheral neuropathy had complete resolution, 14% had partial improvement, and 14% had no improvement. The median time to partial improvement was 2.9 months (range, <1–50), and the median time to complete resolution was 6.6 months (range, <1–67). Of the patients with ongoing neuropathy (28%), 57% had Grade 1, 30% had Grade 2, 12% had Grade 3, and <1% had Grade 4.

In ECHELON-2 (Study 6), 52% of patients treated with ADCETRIS + CHP experienced new or worsening peripheral neuropathy of any grade (by maximum grade, 34% Grade 1, 15% Grade 2, 3% Grade 3, <1% Grade 4). The peripheral neuropathy was predominantly sensory (94% sensory, 16% motor) and had a median onset time of 2 months (range, <1–5). At last evaluation, 50% had complete resolution of neuropathy, 12% had partial improvement, and 38% had no improvement. The median time to resolution or improvement overall was 4 months (range, 0–45). Of patients with ongoing neuropathy (50%), 72% had Grade 1, 25% had Grade 2, and 3% had Grade 3.

In AHOD1331 (Study 7), 20% of pediatric patients treated with ADCETRIS + AVEPC experienced peripheral neuropathy of any grade (7% Grade 3, <1% Grade 4). Peripheral neuropathy was predominantly sensory. Of the patients who experienced peripheral neuropathy, 81% experienced sensory neuropathy and 29% experienced motor neuropathy.

Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.2 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, interrupt the infusion and institute appropriate medical management. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

5.3 Hematologic Toxicities

Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS.

Start primary prophylaxis with G‑CSF beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III or IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

Monitor complete blood counts prior to each dose of ADCETRIS. Monitor more frequently 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 [see Dosage and Administration (2.2, 2.3)].

5.4 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. Monitor patients closely during treatment for the emergence of possible bacterial, fungal, or viral infections.

5.5 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.

5.6 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 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 (CrCL) <30 mL/min] [see Use in Specific Populations (8.6)].

5.7 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 and 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 [see Use in Specific Populations (8.7)].

5.8 Hepatotoxicity

Fatal and serious cases of hepatotoxicity 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.

5.9 Progressive Multifocal Leukoencephalopathy

Fatal cases of JC virus infection resulting in PML have 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.

5.10 Pulmonary Toxicity

Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), 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.

5.11 Serious Dermatologic Reactions

Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

5.12 Gastrointestinal Complications

Fatal and serious events of acute pancreatitis have been reported. Other fatal and serious gastrointestinal (GI) complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

5.13 Hyperglycemia

Serious events of hyperglycemia, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported in ADCETRIS-treated patients. In studies of ADCETRIS monotherapy, 8% of patients experienced any grade hyperglycemia, with 6% experiencing Grade 3 or 4 hyperglycemia. The median time to onset for any grade or Grade 3 or 4 was 1 month (range, 0-10). Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

5.14 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. In animal reproduction studies, brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability, and fetal malformations at maternal exposures that were similar to the clinical dose of 1.8 mg/kg every three weeks.

Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS. Advise a pregnant woman of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended ADCETRIS dosage is provided in Table 1. Administer ADCETRIS as a 30-minute intravenous infusion.

For recommended dosage for patients with renal or hepatic impairment, see Dosage and Administration (2.2 and 2.3).

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

Table 1: Recommended ADCETRIS Dosage

The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
Indication	Recommended Dose*	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 lymphomaconsolidation	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 Hodgkinlymphoma	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 6 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

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 [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.7)].

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.

2.5 Dosage Modifications for Adverse Reactions

Table 2: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Adult Patients

Recommended ADCETRIS Dosage fromTable 1*	MonotherapyorCombination Therapy	Severity	Dosage Modification
The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
Peripheral 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
1.8 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 Motor neuropathy: 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 Motor neuropathy: Discontinue dosing
Grade 4	Discontinue dosing
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
1.8 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
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 Consider G-CSF prophylaxis for subsequent cycles
Recurrent 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

The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. † Peripheral neuropathy was assessed using the Balis scale.
Recommended ADCETRIS Dosage from ***Table 1	Severity	Dosage Modification
Peripheral Neuropathy**†**
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 ADCETRIS If neuropathy improves to Grade ≤1 by day 8 of next cycle, then resume vincristine at full dose
Grade 3**†**	Discontinue vincristine First Occurrence: 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.

Reconstitution

• Follow procedures for proper handling and disposal of hazardous drugs [see References (15)].

• 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 [see Dosage and Administration (2.1)].

• Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection, USP, 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.DO NOT SHAKE.

• 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 at 2° to 8°C (36° to 46°F) and use within 24 hours of reconstitution.DO NOT FREEZE.

• Discard any unused portion left in the vial.

Dilution

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

• Withdraw this amount from the vial and immediately add it to an infusion bag containing 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer's Injection, USP to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.

• Gently invert the bag to mix the solution.

• Following dilution, infuse the ADCETRIS solution immediately. If not used immediately, store the solution at 2° to 8°C (36° to 46°F) and use within 24 hours of reconstitution.DO NOT FREEZE.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. 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 (see Data). 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.

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 cHL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

8.2 Lactation

Risk Summary

There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during ADCETRIS treatment.

8.3 Females and Males of Reproductive Potential

ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].

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 4 months after the last dose of ADCETRIS [see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), ADCETRIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

Males

Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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. The safety and effectiveness of ADCETRIS have not been established for all other indications [see Indications and Usage (1)].

Previously 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 3 to less than 6 years of age, 81 patients 6 to less than 12 years of age, and 345 patients 12 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

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 6 to less than 17 with previously untreated high risk (IIB, IIIB, IVA, or IVB) cHL. No new safety signals were identified in this study.

Relapsed or Refractory Classical 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 5 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.

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 8 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.

Relapsed or Refractory Systemic 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 7 to less than 17 with sALCL. No new safety signals were identified in this study.

Newly Diagnosed 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 2 to less than 17 years with newly diagnosed ALK+ ALCL. No new safety signals were identified in this study.

8.5 Geriatric Use

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 65 or older. Older age was a risk factor for febrile neutropenia, occurring in 39% of patients who were age 65 or older versus 17% of patients less than age 65, who received ADCETRIS + AVD [see Dosage and Administration (2.3)]. The ECHELON-1 trial did not contain sufficient information on patients age 65 and older to determine whether they respond differently from younger patients [see Clinical Studies (14.1)].

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 65 or older. Among older patients, 74% had adverse reactions ≥ Grade 3 and 49% had serious adverse reactions. Among patients younger than age 65, 62% had adverse reactions ≥ Grade 3 and 33% had serious adverse reactions. Older age was a risk factor for febrile neutropenia, occurring in 29% of patients who were age 65 or 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 65 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 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients.

8.6 Renal Impairment

Avoid the use of ADCETRIS in patients with severe renal impairment (CrCL <30 mL/min) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is required for mild (CrCL >50–80 mL/min) or moderate (CrCL 30–50 mL/min) renal impairment.

8.7 Hepatic Impairment

Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. Dosage reduction is required in patients with mild (Child-Pugh A) hepatic impairment [see Dosage and Administration (2.1)].

11 DESCRIPTION

ADCETRIS (brentuximab vedotin) is a CD30-directed antibody and microtubule inhibitor conjugate consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10.

Brentuximab vedotin has an approximate molecular weight of 153 kDa. Approximately 4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

ADCETRIS (brentuximab vedotin) for injection is supplied as a sterile, white to off-white, preservative-free lyophilized cake or powder in single-dose vials. Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.

MMAE was 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 agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies indicate the potential for brentuximab vedotin to impair female and male reproductive function and fertility. In a 4-week repeat-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 mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on body weight.

MMAE-containing ADCs have been associated with adverse ovarian effects when administered to sexually immature animals. Adverse effects included decrease in, or absence of, secondary and tertiary ovarian follicles after weekly administration to cynomolgus monkeys in studies of 4-week duration. These effects showed a trend towards recovery 6 weeks after the end of dosing; no changes were observed in primordial follicles.

14 CLINICAL STUDIES

14.1 Classical Hodgkin Lymphoma

Randomized Clinical Trial in Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON-1, NCT01712490)

The efficacy of ADCETRIS in combination with chemotherapy for the treatment of patients with previously untreated Stage III or IV cHL was evaluated in a randomized, open-label, 2-arm, multicenter trial. Of the 1334 total patients, 664 patients were randomized to the ADCETRIS + doxorubicin [A], vinblastine [V] and dacarbazine [D] (ADCETRIS + AVD) arm and 670 patients were randomized to the A+ bleomycin [B] + V + D (ABVD) arm. Patients in both treatment arms were treated intravenously on Days 1 and 15 of each 28-day cycle for up to 6 cycles. Dosing in each treatment arm was administered according to the following:

• ADCETRIS + AVD arm: ADCETRIS 1.2 mg/kg over 30 minutes, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2
• ABVD arm: doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2

Efficacy was established based on modified progression-free survival (modified PFS) per independent review facility (IRF). A modified PFS event is defined as progression, death, or receipt of additional anticancer therapy for patients who are not in a complete response (CR) after completion of frontline therapy.

Patients had Stage III (36%) or IV disease (64%), and 62% had extranodal involvement at diagnosis. Most patients were male (58%) and white (84%). The median age was 36 years (range, 18‑83); 186 patients (14%) were 60 years or older.

The efficacy results are summarized in Table 11. and Figure 1.

Table 11: Efficacy Results in Patients with Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON‑1)

*Not estimable + At the time of analysis, the median follow-up time for both arms was 24.6 months a Hazard ratio (A+AVD/ABVD) and 95% confidence intervals are based on a stratified Cox’s proportional hazard regression model with stratification factors region and number of International Prognostic Factor Project (IPFP) risk factors at baseline with treatment as the explanatory variable in the model. b P-value is from a stratified log-rank test with stratification factors baseline IPFP group and region; alpha = 0.05.
Modified Progression-Free Survival per IRF+	ADCETRIS + AVD N=664	ABVD N=670
Number of events (%)	117 (18%)	146 (22%)
Median months (95% CI)	NE*	NE*
Hazard ratio (95% CI)a	0.77 (0.60, 0.98)
P-valueb	0.035
Reason leading to a modified PFS event
Progressive disease	90 (14)	102 (15)
Death due to any cause	18 (3)	22 (3)
Receipt of additional anticancer therapy for patients not in CR after frontline therapy	9 (1)	22 (3)

At the time of the modified PFS analysis, the prespecified interim OS analysis did not demonstrate a significant difference. The CR rate per IRF assessment at the end of the randomized regimen was 73% on the ADCETRIS + AVD arm and 70% on the ABVD arm.

A prespecified second interim analysis showed a statistically significant improvement in OS in the ADCETRIS + AVD arm (39 deaths) compared to the ABVD arm (64 deaths). With an estimated median follow-up of 6.1 years, the stratified hazard ratio was 0.59 (95% CI, 0.396; 0.879), with a 2-sided p-value of 0.009 (significance level, 0.0365). Median OS was not reached in either treatment arm (Figure 2).

Randomized Clinical Trial in Previously Untreated High Risk Classical Hodgkin Lymphoma (Study 7, AHOD1331, NCT02166463)

The efficacy of ADCETRIS in combination with chemotherapy for the treatment of pediatric patients (2 to <22 years of age) with previously untreated high risk cHL was evaluated in a randomized, open-label, actively controlled trial. High risk was defined as Ann Arbor Stage IIB with bulk disease, Stage IIIB, Stage IVA, and Stage IVB. Of the 600 total patients randomized, 300 were randomized to ADCETRIS + Doxorubicin [A], Vincristine [V], Etoposide [E], Prednisone [P], Cyclophosphamide [C] (ADCETRIS + AVEPC) arm and 300 patients were randomized to A+ Bleomycin [B]+V+E+P+C (ABVE-PC) arm. Patients in each treatment arm received up to 5 cycles of the following:

• ADCETRIS + AVEPC arm: ADCETRIS 1.8 mg/kg over 30 minutes (day 1), doxorubicin 25 mg/m2 (days 1 and 2), vincristine 1.4 mg/m2 (day 8), etoposide 125 mg/m2 (days 1-3), prednisone 20 mg/m2 BID (days 1-7), cyclophosphamide 600 mg/m2​ (days 1 and 2)
• ABVE-PC arm: doxorubicin 25 mg/m2 (days 1 and 2), bleomycin 5 units/m2 (day1) and 10 units/m2 (day 8), vincristine 1.4 mg/m2 (days 1 and 8), etoposide 125 mg/m2 (days 1-3), prednisone 20 mg/m2 BID (days 1-7), cyclophosphamide 600 mg/m2 (days 1 and 2)​

The median age was 15 years (range: 3-21 years); 53% were male, 74% were White, 11% Black, and 3% Asian. Nine patients were <6 years, 81 patients were 6 to <12 years, 448 patients were 12 to <18 years, and 62 patients were ≥18 years. ​Of the 600 enrolled patients, 20% had disease stage of IIB with bulk disease, 19% had IIIB, 29% had IVA, and 31% had IVB.

Efficacy was established based on event-free-survival (EFS), defined as the time from randomization to the earliest of disease progression or relapse, second malignancy, or death due to any cause. Efficacy results are summarized in Table 12.

Table 12: Efficacy Results in Pediatric Patients with Previously Untreated High Risk Classical Hodgkin Lymphoma (Study 7: AHOD1331)

NR Not reached
a Hazard ratio (BV-AVEPC/ABVE-PC) and 95% confidence intervals are based on a Cox proportional hazard regression model stratified by clinical characteristics (Stage IIB with bulk vs. Stage IIIB vs. Stage IVA vs. Stage IVB) as
recorded at randomization
b Two-sided p-value from log-rank test stratified by clinical characteristic (disease stage).
Event-Free Survival****​	ADCETRIS + AVEPC****​ ******N =**​ 300	ABVE-PC ****​**N =**​ 300
Number of Events (%)​	​23 (8)	​52 (17)
Median (95% CI)	​NR	​NR
Hazard Ratio (95% CI)​a	​0.41 (0.25, 0.67)
P-value (log-rank test)​b	​0.0002

Randomized Placebo-Controlled Clinical Trial in Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA, NCT01100502)

The efficacy of ADCETRIS in patients with cHL at high risk of relapse or disease progression post-auto-HSCT was studied in a randomized, double-blind, placebo-controlled clinical trial. Three hundred twenty-nine (329) patients were randomized 1:1 to receive placebo or ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles, beginning 30–45 days post- auto-HSCT. Patients in the placebo arm with progressive disease per investigator could receive ADCETRIS as part of a separate trial. The primary endpoint was progression-free survival (PFS) determined by independent review facility (IRF). Standard international guidelines were followed for infection prophylaxis for HSV, VZV, and PJP post-auto-HSCT [see Clinical Trial Experience (6.1)].

High risk of post-auto-HSCT relapse or progression was defined according to status following frontline therapy: refractory, relapse within 12 months, or relapse ≥12 months with extranodal disease. Patients were required to have obtained a complete response (CR), partial response (PR), or stable disease (SD) to most recent pre-auto-HSCT salvage therapy.

A total of 329 patients were enrolled and randomized (165 ADCETRIS, 164 placebo); 327 patients received study treatment. Patient demographics and baseline characteristics were generally balanced between treatment arms. The 329 patients ranged in age from 18–76 years (median, 32 years) and most were male (53%) and white (94%). Patients had received a median of 2 prior systemic therapies (range, 2–8) excluding autologous hematopoietic stem cell transplantation.

The efficacy results are summarized in Table 13. PFS is calculated from randomization to date of disease progression or death (due to any cause). The median PFS follow-up time from randomization was 22 months (range, 0–49). Study 3 (AETHERA) demonstrated a statistically significant improvement in IRF- assessed PFS and increase in median PFS in the ADCETRIS arm compared with the placebo arm. At the time of the PFS analysis, an interim overall survival analysis demonstrated no difference.

Table 13: Efficacy Results in Patients with Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA)

Progression-Free Survival per IRF	ADCETRIS ****N = 165	Placebo ****N = 164
Number of events (%)	60 (36)	75 (46)
Median months (95% CI)	42.9+ (30.4, 42.9+)	24.1 (11.5, NE* )
Stratified Hazard Ratio (95% CI)	0.57 (0.40, 0.81)
Stratified Log-Rank Test P-value	0.001

• Not estimable
  + Estimates are unreliable

Clinical Trial in Relapsed Classical Hodgkin Lymphoma (Study 1, NCT00848926)

The efficacy of ADCETRIS in patients with cHL who relapsed after autologous hematopoietic stem cell transplantation was evaluated in one open-label, single-arm, multicenter trial. One hundred two (102) patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks. An independent review facility (IRF) performed efficacy evaluations which included overall response rate (ORR = complete response [CR] + partial response [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

The 102 patients ranged in age from 15–77 years (median, 31 years) and most were female (53%) and white (87%). Patients had received a median of 5 prior therapies including autologous hematopoietic stem cell transplantation.

The efficacy results are summarized in Table 14. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 14: Efficacy Results in Patients with Classical Hodgkin Lymphoma (Study 1)

*Not estimable +Follow up was ongoing at the time of data submission
	N = 102
Percent (95% CI)	Duration of Response, in months
Median (95% CI)	Range
CR	32 (23, 42)	20.5 (12.0, NE*)	1.4 to 21.9+
PR	40 (32, 49)	3.5 (2.2, 4.1)	1.3 to 18.7
ORR	73 (65, 83)	6.7 (4.0, 14.8)	1.3 to 21.9+

14.2 Systemic Anaplastic Large Cell Lymphoma and Other CD30-Expressing

Peripheral T-Cell Lymphomas

Randomized Clinical Trial in Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas (Study 6: ECHELON-2, NCT01777152)

The efficacy of ADCETRIS in combination with chemotherapy for the treatment of adult patients with previously untreated, CD30-expressing PTCL was evaluated in a multicenter, randomized, double-blind, double-dummy, actively controlled trial. For enrollment, the trial required CD30 expression ≥10% per immunohistochemistry. The trial excluded patients with primary cutaneous CD30-positive T-cell lymphoproliferative disorders and lymphomas. The trial required hepatic transaminases ≤3 times ULN, total bilirubin ≤1.5 times ULN, and serum creatinine ≤2 times ULN.

Of the 452 total patients, 226 patients were randomized to the ADCETRIS + CHP arm and 226 patients were randomized to the CHOP arm. Patients in both treatment arms were treated intravenously on Day 1 of each 21-day cycle for 6 to 8 cycles; prednisone was administered orally on Days 1‑5. Dosing in each treatment arm was administered according to the following:

• ADCETRIS + CHP arm: ADCETRIS 1.8 mg/kg over 30 minutes, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and prednisone 100 mg orally
• CHOP arm: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 100 mg orally

The median age was 58 years (range: 18 to 85), 63% were male, 62% were White, 22% were Asian, and 78% had an ECOG performance status of 0-1. Of the 452 patients enrolled, the disease subtypes included patients with systemic ALCL [70%; 48% anaplastic lymphoma kinase (ALK) negative and 22% ALK positive], PTCL not otherwise specified (16%), angioimmunoblastic T-cell lymphoma (12%), adult T-cell leukemia/lymphoma (2%), and enteropathy-associated T-cell lymphoma (<1%). Most patients had Stage III or IV disease (81%) and a baseline international prognostic index of 2 or 3 (63%).

During randomized treatment, on the ADCETRIS + CHP arm, 70% of patients received 6 cycles and 18% of patients received 8 cycles. On the CHOP arm, 62% of patients received 6 cycles and 19% received 8 cycles.

Efficacy was based on IRF-assessed PFS, which was defined as time from randomization to progression, death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease. Other efficacy endpoints included PFS in patients with systemic ALCL, overall survival, complete response rate, and overall response rate. Efficacy results are summarized in Table 15. Kaplan-Meier curves for PFS and overall survival are presented in Figure 5 and Figure 6 respectively.

Table 15: Efficacy Results in Patients with Previously Untreated, CD30-Expressing PTCL (Study 6: ECHELON‑2)

NE: Not estimable
a Efficacy endpoints were tested at a two-sided alpha level 0.05 in the following order: PFS in ITT, PFS in the sALCL subgroup, complete remission rate, overall survival, and objective response rate in ITT.
b Hazard ratio (A+CHP/CHOP) and 95% confidence intervals are based on a stratified Cox’s proportional hazard regression model with the following stratification factors (ALK- positive sALCL and International Prognostic Index [IPI] score at baseline).
c P-value is calculated using a stratified log-rank test.
d Median OS follow-up in the ADCETRIS+CHP arm was 41.9 months; in the CHOP arm was 42.2 months.
e Best response per 2007 International Working Group Criteria at end of treatment.
f P-value is calculated using a stratified Cochran-Mantel-Haenszel test
Outcomes per IRF****a	ADCETRIS + CHP N=226	CHOP N=226
PFS
Number of events, n (%)	95 (42)	124 (55)
Median PFS, months (95% CI)	48.2 (35.2, NE)	20.8 (12.7, 47.6)
Hazard ratio (95% CI)b	0.71 (0.54, 0.93)
P-valuec	0.011
Reason leading to a PFS event, n (%)
****Progressive disease	71 (31)	86 (38)
Death	13 (6)	17 (8)
Receipt of subsequent anticancer chemotherapy to treat residual or progressive disease	11 (5)	21 (9)
PFS for patients with sALCL
N	163	151
Number of patients with a PFS event, n (%)	56 (34)	73 (48)
Median PFS, months (95% CI)	55.7 (48.2, NE)	54.2 (13.4, NE)
Hazard ratio (95% CI)b	0.59 (0.42, 0.84)
P-valuec	0.003
OSd
Number of deaths	51 (23)	73 (32)
Median OS, months (95% CI)	NE (NE, NE)	NE (54.2, NE)
Hazard ratio (95% CI)b	0.66 (0.46, 0.95)
P-valuec	0.024
CR Ratee
% (95% CI)	68 (61, 74)	56 (49, 62)
P-valuef	0.007
ORRe
% (95% CI)	83 (78, 88)	72 (66, 78)
P-valuef	0.003

14.3 Systemic Anaplastic Large Cell Lymphoma

Clinical Trial in Relapsed sALCL (Study 2, NCT00866047)

The efficacy of ADCETRIS in patients with relapsed sALCL was evaluated in one open-label, single-arm, multicenter trial. This trial included patients who had sALCL that was relapsed after prior therapy. Fifty-eight (58) patients were treated with 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. An IRF performed efficacy evaluations which included overall response rate (ORR = complete response [CR] + partial response [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

The 58 patients ranged in age from 14–76 years (median, 52 years) and most were male (57%) and white (83%). Patients had received a median of 2 prior therapies; 26% of patients had received prior autologous hematopoietic stem cell transplantation. Fifty percent (50%) of patients were relapsed, and 50% of patients were refractory to their most recent prior therapy. Seventy-two percent (72%) were anaplastic lymphoma kinase (ALK)-negative.

The efficacy results are summarized in Table 16. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 16: Efficacy Results in Patients with Systemic Anaplastic Large Cell Lymphoma (Study 2)

	N = 58
Percent (95% CI)	Duration of Response, in months
Median (95% CI)	Range
*Not estimable + Follow up was ongoing at the time of data submission
CR	57 (44, 70)	13.2 (10.8, NE*)	0.7 to 15.9+
PR	29 (18, 41)	2.1 (1.3, 5.7)	0.1 to 15.8+
ORR	86 (77, 95)	12.6 (5.7, NE*)	0.1 to 15.9+

14.4 Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-Expressing

Mycosis Fungoides

Randomized Clinical Trial in Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides (Study 4: ALCANZA, NCT01578499)

The efficacy of ADCETRIS in patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF) requiring systemic therapy was studied in ALCANZA, a randomized, open-label, multicenter clinical trial. In ALCANZA, one hundred thirty-one (131) patients were randomized 1:1 to receive ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks or physician’s choice of methotrexate (5 to 50 mg orally weekly) or bexarotene (300 mg/m2 orally daily). The randomization was stratified by baseline disease diagnosis (MF or pcALCL). Patients could receive a maximum of 16 cycles (21-day cycle) of therapy every 3 weeks for those receiving brentuximab vedotin or 48 weeks of therapy for those in the control arm.

Patients with pcALCL must have received prior radiation or systemic therapy, and must have at least 1 biopsy with CD30-expression of ≥10%. Patients with MF must have received prior systemic therapy and have had skin biopsies from at least 2 separate lesions, with CD30-expression of ≥10% in at least 1 biopsy.

A total of 131 patients were randomized (66 ADCETRIS, 65 physician’s choice). The efficacy results were based on 128 patients (64 patients in each arm with CD30-expression of ≥10% in at least one biopsy). Among 128 patients, the patients’ age ranged from 22–83 years (median, 60 years), and 55% of them were male and 85% of them were white. Patients had received a median of 4 prior therapies (range, 0–15), including a median of 1 prior skin-directed therapy (range, 0–9) and 2 systemic therapies (range, 0–11). At study entry, patients were diagnosed as Stage 1 (25%), Stage 2 (38%), Stage 3 (5%), or Stage 4 (13%).

Efficacy was established based on the proportion of patients achieving an objective response (CR+PR) that lasts at least 4 months (ORR4). ORR4 was determined by independent review facility (IRF) using the global response score (GRS), consisting of skin evaluations per modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic assessment, and detection of circulating Sézary cells (MF patients only). Additional efficacy outcome measures included proportion of patients achieving a complete response (CR) per IRF, and progression-free survival (PFS) per IRF.

The efficacy results are summarized in Table 17 below and the Kaplan-Meier curves of IRF-assessed PFS are shown in Figure 7.

Table 17: Efficacy Results in Patients with Relapsed pcALCL or CD30-Expressing MF (Study 4: ALCANZA)

a Physician’s choice of either methotrexate or bexarotene b ORR4 is defined as proportion of patients achieving an objective response (CR+PR) that lasts at least 4 months c CI=Confidence Interval d Test of the treatment difference was stratified by baseline disease diagnosis (MF or pcALCL) e Adjusted for multiplicity
	ADCETRIS ****N = 64	Physician’s Choice****a N = 64
ORR4b
Percent (95% CIc)	56.3 (44.1, 68.4)	12.5 (4.4, 20.6)
P-valued	<0.001
ORR	67.2 (55.7, 78.7)	20.3 (10.5, 30.2)
CR
Percent (95% CIc)	15.6 (7.8, 26.9)	1.6 (0, 8.4)
P-valued,e	0.0066
PR	51.6 (39.3, 63.8)	18.8 (9.2, 28.3)
PFS
Number of events (%)	36 (56.3)	50 (78.1)
Median months (95% CIc)	16.7 (14.9, 22.8)	3.5 (2.4, 4.6)
Hazard Ratio (95% CIc)	0.27 (0.17, 0.43)
Log-Rank Test P-valued,e	<0.001

Supportive trials include 2 single-arm trials, which enrolled patients with MF who were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks. Out of 73 patients with MF from the 2 pooled supportive trials, 34% (25/73) achieved ORR4. Among these 73 patients, 35 had 1% to 9% CD30-expression and 31% (11/35) achieved ORR4.

17 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 [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.2)].

Hepatotoxicity

Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.8)].

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 [see Boxed Warning, Warnings and Precautions (5.9)]:

• 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 [see Warnings and Precautions (5.10)].

Acute Pancreatitis

Advise patients to contact their health care provider if they develop severe abdominal pain [see Warnings and Precautions (5.12)].

Gastrointestinal Complications

Advise patients to contact their health care provider if they develop severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea [see Warnings and Precautions (5.12)].

Hyperglycemia

Educate patients about the risk of hyperglycemia and how to recognize associated symptoms [see Warnings and Precautions (5.13)].

Females and Males of Reproductive Potential

ADCETRIS can cause fetal harm. Advise women receiving ADCETRIS to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS [see Use in Specific Populations (8.3)].

Advise patients to report pregnancy immediately [see Warnings and Precautions (5.14)].

Lactation

Advise patients to avoid breastfeeding while receiving ADCETRIS [see Use in Specific Populations (8.2)].

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