Adcetris

Brentuximab (Adcetris) instructions
Common name: brentuximab vedotin
Trade name: Adcetris
All names: brentuximab, brentuximab, CD30 monoclonal antibody, Adcetris, brentuximab vedotin

Indications:
(1) Classical Hodgkin lymphoma (CHL)
Previously untreated CHL
First-line treatment in combination with doxorubicin, vinblastine and dacarbazine (AVD) for the treatment of previously untreated stage III or IV CHL

CHL combined
Indicated for post-autologous hematopoietic stem cell transplant (auto-HSCT) combined patients with high recurrence or progression Risky cHL

Recurrent CHL
Non-automatic HSCT candidates showing CHL after failure of automatic HSCT or after failure of at least 2 prior multiagent chemotherapy regimens

(2) Systemic anaplastic large cell lymphoma (sALCL)
Untreated sALCL
Indicated for previously untreated systemic anaplastic large cell lymphoma (sALCL)

< br>Relapsed sALCL
Indicated for the treatment of systemic anaplastic large cell lymphoma (sALCL) after failure of at least one previous multi-agent chemotherapy regimen

(3) Primary cutaneous anaplastic large cell lymphoma
Applicable to primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycotic fungi (MF) who have received previous systemic therapy

(4) Expression of C D30 for Peripheral T-Cell Lymphoma
In combination with cyclophosphamide, doxorubicin, and prednisone (CHP) for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified

Dosage:
Classic Hodgkin lymphoma (cHL)
Previously untreated CHL
Intravenous infusion of 1.2 every 2 weeks mg/kg (in combination with AVD); not to exceed 120 mg/dose

Continue until maximum dose of 12 doses, disease progression, or unacceptable toxicity

cHL combined
Initiate within 4-6 weeks after automated HSCT or after recovery from automated HSCT
1.8 mg/kg intravenously every three weeks; Not to exceed 180 mg/dose

Continue until up to 16 cycles, disease progression or unacceptable toxicity

Recurrent cHL
1.8 mg/kg IV every three weeks; Not to exceed 180 mg/dose

Continue until disease progression or unacceptable toxicity

Systemic Anaplastic Large Cell Lymphoma
Untreated Systemic Anaplastic Large Cell Lymphoma (sALCL)

1.8 mg/IV every three weeks kg, 6 to 8 doses; not to exceed 180 mg/dose

Relapsed sALCL
1.8 mg/kg IV every three weeks; not to exceed 180 mg/dose

Continue until disease progression or unacceptable toxicity

Primary cutaneous anaplastic large cell lymphoma
1.8 mg/kg IV every three weeks; Not to exceed 180 mg/dose

Continue until up to 16 cycles, disease progression or unacceptable toxicity

CD30-expressing peripheral T-cell lymphoma

1.8 mg/d IV every three weeks kg, 6-8 doses; not to exceed 180 mg/dose

Dose adjustment
Renal insufficiency
1.2 mg/kg every 2 weeks or 1.8 mg/kg every 3 weeks
Mild or moderate (CrCl 30-80 mL/min): No dose adjustment required

Severe (CrCl<30 mL/min): Avoid use

Hepatic Impairment
Mild (Child-Pugh A)
1.2 mg/kg every 2 weeks: 0.9 mg/kg every 2 weeks; Not to exceed 90 mg/dose
1.8 mg/kg every 3 weeks: 1.2 mg/kg every 3 weeks; not to exceed 120 mg/dose

Moderate or severe (Child-Pugh B or C): Avoid use

Peripheral neuropathy

Monotherapy (1.8 mg/kg Every 3 weeks)
New or worsening Grade 2 or 3: Maintain dose until neuropathy improves to Grade 1 or baseline; start at 1.2 mg/kg (not to exceed 120 mg /dose) Restart

Grade 4: Discontinue brentuximab

Combination therapy (1.2 mg/kg every 2 weeks)
Grade 2: Reduce dose to 0.9 mg/kg/dose every 2 weeks; not to exceed 90 mg/dose
Grade 3: Maintain dose until neuropathy improves below Grade 2; restart at 0.9 mg/kg every 2 weeks (not to exceed 90 mg/dose) /dose); consider changing the dose of other neurotoxic chemotherapy

Level 4: Discontinue brentuximab

Combination therapy (1.8 mg/kg every 3 weeks)
Grade 2 sensory neuropathy: no dose adjustment required
Grade 2 motor neuropathy or grade 3 sensory neuropathy: reduce to 1.2 mg/kg weekly kg (not to exceed 120 mg/dose)

Grade 3 motor neuropathy or grade 4 peripheral neuropathy: Discontinue brentuximab

Neutropenia
Combination therapy (1.8 mg/kg per week or 1.2 mg/kg per week) kg)

Grade ≥3: For patients not receiving primary G-CSF prophylaxis, administer G-CSF prophylaxis in subsequent cycles

Monotherapy (1.8 mg/kg every 3 weeks)
Grade ≥3 neutropenia: Maintain dose until baseline or ≤grade 2; consider G-CSF prophylaxis for subsequent cycles
Recurrent grade 4 (despite G-CSF prophylaxis): Consider discontinuation of brentuximab or reduction to 1.2 mg/kg per week (not to exceed 120 mg/dose per week)

Adverse Reactions:
> 10% (untreated cHL, any grade)
Anemia (98%)
Neutropenia (91%)
Peripheral sensory neuropathy (65%)
Constipation (42%)
Vomiting (33%)
Diarrhea (27%)
Fever (27%)
Weight loss (22%)
Stomatitis (21%)
Abdominal pain (21%)
Febrile neutropenia (19%)
Bone pain (19%)
Insomnia (19%)
Decreased appetite (18%)
Back pain (13%)
Rash, outbreak, fever (13%)
Dyspnea (12%)
Peripheral motor neuropathy (11%)

> 10% (untreated cHL, grade 3 or 4)
Neutropenia (20-62%)
Febrile neutropenia (6-13%)
Anemia (1-11%)

> 10% (pcALCA or MF, any grade)
Anemia (62%)
Peripheral sensory neuropathy (45%)
Nausea (36%)
Diarrhea (29%)
Fatigue (29%)
Neutropenia (21%)
Vomiting (1 7%)
Pruritus (17%)
Fever (17%)
Alopecia (15%)
Thrombocytopenia (15%)
Decreased appetite (15%)
Arthralgia (12%)
Myalgia (12%)
Peripheral edema (11%)
Maculopapular rash (11%)
Generalized pruritus (11%)
Asthenia (11%)
Dyspnea (11%)

1-10% (untreated cHL)
Increased ALT in all grades (10%)
3rd or 4th grade
Peripheral sensory neuropathy (10%)
Vomiting (3%)
Diarrhea (3%)
Abdominal pain (3%)
Increased ALT (3%)
Fever (3%)
Constipation (2%)Stomatitis (2%)
Peripheral motor neuropathy (2%)
Dyspnea (1%)

1-10% (other indications)
Extremity pain (10%)
Muscle spasm (9-10%)
Dry skin (4-10%)
Chills (4%)
Nausea (3–4%)
Difficulty breathing (2-3%)
Itching (2–5%)
Fever (2%)
Cough (2%)
Grade 3 or 4 (pcAL CL or MF)
Peripheral sensory neuropathy (5%)
Fatigue (5%)
Diarrhea (3%)
Neutropenia (2-3%)
Asthenia (2%)
Maculopapular rash (2%)
Generalized pruritus (2%) )
Nausea (2%)
Vomiting (2%)
Thrombocytopenia (2%)

Postmarketing Reports
Haematological and lymphatic system abnormalities: febrile neutropenia
Gastrointestinal disorders: acute pancreatitis and gastric Intestinal complications (including fatal outcomes)
Hepatobiliary diseases: hepatotoxicity
Infections: PML, serious infections and opportunistic infections
Metabolic and nutritional disorders: hyperglycemia
Respiratory, thoracic and mediastinal diseases: non-infectious pulmonary toxicities, including pneumonitis, interstitial Pulmonary diseases and ARDS (some with fatal consequences)
Skin and subcutaneous tissue disorders: toxic epidermal necrosis, including fatal consequences

Contraindications:
Concomitant use of brentuximab and bleomyc due to pulmonary toxicity in

Notes:
Peripheral neuropathy (primarily sensory neuropathy) and motor neuropathy have been reported; drug-induced peripheral neuropathy is cumulative; monitor for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesias, malaise , burning sensation, neuropathic pain, weakness)
Cases of fatal and severe febrile neutropenia have been reported; monitor complete blood count (CBC) before each dose; in patients who have not previously received stage III or IV cHL or who have not been previously treated for PTCL Patients on chemotherapy drugs, starting with cycle 1 for primary prevention with G-CSF
Grade 3 or 4 thrombocytopenia or anemia may occur
The frequency of grade 3 adverse reactions and death in patients with severe renal or hepatic impairment has been reported to be higher than in patients with normal renal/hepatic function Cases of severe hepatotoxicity, including fatal outcomes reported after the first dose or after rechallenge; Cases of severe hepatotoxicity, including fatal consequences; Preexisting liver disease, elevated baseline liver enzymes, and concomitant use may increase risk; Monitor liver enzymes and bilirubin; Development of new, malignant Patients with progressive or recurrent hepatotoxicity may require treatment delays, dose changes, or discontinuation of treatment
JC virus infection causing progressive multifocal leukoencephalopathy (PML) and death has been reported (see Black Box Warning)
Closely monitor for bacterial, fungal, or viral infections Non-infectious pulmonary toxic events (e.g., pneumonia, interstitial lung disease, acute respiratory distress syndrome [ARDS]), some with fatal consequences, have been reported
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis Fatal and serious cases of (TEN); if SJS or TEN occurs, discontinue treatment and initiate appropriate medical therapy
Reports of acute pancreatitis, including fatal consequences
Fatal and serious gastrointestinal (GI) complications (e.g., perforation, bleeding, erosions) have been reported ulcers, intestinal obstruction, enterocolitis, neutrophilic colitis and intestinal obstruction); Lymphoma with gastrointestinal involvement may increase the risk of perforation; promptly evaluate for new or worsening gastrointestinal symptoms and treat appropriately
Potential harm to the fetus
Patients with rapid tumor proliferation and high tumor burden are at risk for tumor lysis syndrome; monitor closely and treat appropriately
Severe hyperglycemic events (e.g., new-onset hyperglycemia), exacerbation of preexisting diabetes, and ketoacidosis (including fatal outcomes) have been reported; high body mass index or glucose More commonly seen in patients with diabetes; monitor blood glucose and, if hyperglycemia occurs, take antihyperglycemic medications as clinically indicated

Infusion-related reactions
Infusion-related reactions (e.g., anaphylaxis) may occur
If an allergic reaction occurs, seek immediate medical attention immediately Discontinue treatment for a long time
If an infusion-related reaction occurs, interrupt the infusion
After interrupting or discontinuing treatment, provide appropriate medical management
Premedication for patients who have previously experienced an infusion-related reaction subsequent infusion
Prescribed medications may include acetaminophen, antimicrobials Amines and Corticosteroids

Drug Interaction Overview
Strong CYP3A4 Inhibitors
Coadministration with the strong CYP3A4 inhibitor ketoconazole increases exposure to MMAE, which may increase the risk of adverse reactions
With Strong CYP3A4 Inhibitors Adverse reactions should be closely monitored when 3A4 inhibitors are used concomitantly

Black box warning
Progressive multifocal leukoencephalopathy
Potential risk of JC virus infection leading to PML and death; Progressive multifocal leukoencephalopathy (PML) case report
P ML is a rare but serious brain infection that can lead to death
Signs and symptoms of PML may last for weeks or months and may include mood changes, unusual behavior, confusion, thinking problems, memory loss, changes in vision, speech, or walking, and unilateral decreases in strength or weakness

Storage:
Unopened vials: Refrigerate in original carton at 2-8°C (36-46°F) to protect from light
Diluted solutions or reconstituted vials: Refrigerate at 2-8°C (36-46°F) for up to 24 hours
No To freeze

Mechanism of action:
CD30-directed antibody-drug conjugate (ADC), composed of the chimeric IgG1 antibody cAC10 specific for human CD30 and the microtubule disrupting agent, monomethyl auristatin E (MMAE or vedotin).
The conjugate binds to cells expressing the CD30 antigen and forms a complex, which is internalized within the cell and releases MMAE. MMAE induces cell cycle (G2/M phase) arrest by binding to tubules and disrupting the cellular microtubule network.

Efficacy and safety:
The approval was based on data from the Phase III clinical study ECHELON-2. This study is the largest randomized, double-blind phase III study conducted in PTCL patients to date. It enrolled patients with CD30-positive PTCL who had not received treatment before. It evaluated the efficacy and safety of Adcetris combined with the chemotherapy regimen CHP (cyclophosphamide + doxorubicin + prednisone) for first-line treatment compared with the currently recognized first-line standard care regimen CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) for the treatment of PTCL. The primary endpoint of the study was progression-free survival (PFS) as assessed by double-blind independent central review (BICR).
The results showed that compared with the CHOP regimen, the Adcetris+CHP regimen achieved a statistically significant improvement in PFS, which was equivalent to a 29% reduction in the risk of disease progression, death, and receipt of subsequent anti-cancer chemotherapy to treat residual or progressive disease (BICR: HR=0.71, 95% CI: 0.54-0.93, p=0.011), reaching the primary endpoint of the study. In addition, compared with the CHOP regimen, the Adcetris+CHP regimen also showed superiority in the key secondary endpoint overall survival (OS) (HR=0.66, 95%CI: 0.46-0.95, p=0.0244). In terms of other key secondary endpoints, the Adcetris+CHP regimen also showed statistically significant advantages, including: PFS (HR=0.59; 95%CI: 0.42-0.84, p=0.003), complete response rate (CRR: 68% vs 56%, p=0.007), and objective response rate (ORR: 83% vs 72%, p=0.003) in patients with sALCL. In this study, the Adcetris+CHP regimen had a comparable safety profile to the CHOP regimen and was consistent with the established safety profile of the Adcetris and chemotherapy combination regimen.