Leukemias, lymphomas, and other hematologic cancers:
Indications for: ADCETRIS
Adults with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine. Pediatric patients aged ≥2yrs with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. Adults with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplant (auto-HSCT) consolidation. Adults with cHL after failure of auto-HSCT or after failure of ≥2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates. Adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone. Adults with sALCL after failure of ≥1 prior multi-agent chemotherapy regimen. Adults with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.
Clinical Trials:
Classical Hodgkin Lymphoma
Randomized Clinical Trial in Previously Untreated Stage III or IV classical Hodgkin Lymphoma (Study 5: ECHELON-1, NCT01712490)
Adcetris in combination with chemotherapy was evaluated in 1334 total patients with previously untreated Stage III or IV cHL in a randomized, open-label, 2-arm, multicenter trial. Patients were randomly assigned 1:1 to receive either Adcetris + AVD (adriamycin, vinblastine, dacarbazine) or ABVD (adriamycin, bleomycin, vinblastine, dacarbazine).
Results showed that the trial met its primary endpoint with Adcetris + AVD achieving a statistically significant improvement in modified progression-free survival (PFS) vs ABVD control (hazard ratio [HR] 0.77, 95% CI, 0.60-0.98; P =.035), corresponding to a 23% reduction in the risk of progression, death or need for additional anti-cancer therapy in patients without complete response (CR) after frontline treatment.
Overall survival (OS), a key secondary endpoint, favored Adcetris + AVD in an interim analysis but the difference was not significant (HR 0.72, 95% CI, 0.44-1.17; P =.19). The CR rate was 73% in the Adcetris + AVD arm vs 70% in the ABVD arm.
Randomized Clinical Trial in Previously Untreated High Risk classical Hodgkin Lymphoma (Study 7, AHOD1331, NCT02166463)
Adcetris in combination with chemotherapy was evaluated in 600 pediatric patients (2 to <22 years of age) with previously untreated high risk cHL in a randomized, open-label, actively controlled trial. Patients were randomly assigned 1:1 to receive either Adcetris plus AVEPC (doxorubicin [A], vincristine [V], etoposide [E], prednisone [P], cyclophosphamide[C]) or A + B (bleomycin) + V + E + P + C (ABVE-PC) for up to 5 cycles.
Results showed treatment with brentuximab vedotin + AVEPC reduced the risk of disease progression or relapse, second malignancy, or death (primary endpoint) by 59% when compared with ABVE-PC (hazard ratio, 0.41 [95% CI, 0.25-0.67]; P =.0002).
Randomized Placebo-Controlled Clinical Trial in classical Hodgkin Lymphoma Post-AutoHSCT Consolidation (Study 3: AETHERA, NCT01100502)
The efficacy of Adcetris was evaluated in 329 patients with cHL at high risk of relapse or disease progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial. Patients were randomly assigned 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. The primary endpoint was progression-free survival (PFS) determined by an independent review facility (IRF).
Results showed that treatment with Adcetris achieved a statistically significant improvement in IRF-assessed PFS vs placebo (stratified hazard ratio, 0.57 [95% CI, 0.40-0.81]; P =.001). The median PFS was 42.9+ months (95% CI, 30.4-42.9+) for the Adcetris arm and 24.1 months (95% CI, 11.5 - Not estimable).
Clinical Trial in Relapsed classical Hodgkin Lymphoma (Study 1, NCT00848926)
The efficacy of Adcetris was evaluated in 102 patients with cHL who relapsed after autologous hematopoietic stem cell transplantation in one open-label, single-arm, multicenter trial. Patients were treated with 1.8 mg/kg of Adcetris IV over 30 minutes every 3 weeks. Patients had received a median of 5 prior therapies including autologous hematopoietic stem cell transplantation.
Results showed an ORR of 73% (95% CI, 65-83), of which 32% of patients achieved complete response and 40% achieved partial response.The median duration of response was 6.7 months (95% CI, 4-14.8)
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 was evaluated in 452 adults with previously untreated, CD30-expressing PTCL in a multicenter, randomized, double-blind, double-dummy, actively controlled trial. Patients were randomly assigned 1:1 to receive either Adcetris + CHP (cyclophosphamide, doxorubicin, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
Results showed PFS was significantly longer (hazard ratio [HR] 0.71 (95% CI, 0.54-0.93; P =.011) in the Adcetris arm (median 48.2 months vs 20.8 months with CHOP). Overall survival (HR 0.66 [95% CI, 0.46, 0.95; P =.024]) and overall response rates (83% vs 72% with CHOP; P =.003) were also significantly better in the Adcetris arm.
Systemic Anaplastic Large Cell Lymphoma
Clinical Trial in Relapsed sALCL (Study 2, NCT00866047)
The efficacy of ADCETRIS was evaluated in 58 patients with relapsed sALCL in one open-label, single-arm, multicenter trial. The trial included patients who had sALCL that were relapsed after prior therapy. Patients received 1.8 mg/kg of Adcetris IV over 30 minutes every 3 weeks.
Results showed an ORR of 86% (95% CI, 77-95), of which 57% of patients achieved complete response (95% CI, 44-70) and 29% achieved partial response (95% CI, 18-41). The median duration of response was 12.6 months.
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 was evaluated in 131 patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF) requiring systemic therapy in ALCANZA, a randomized, open-label, multicenter clinical trial. Patients were randomly assigned 1:1 to receive Adcetris 1.8 mg/kg IV 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 primary endpoint was achieved with Adcetris-treated patients showing a highly statistically significant improvement in objective response rate lasting ≥4 months (ORR4) vs. the control group (56.3% vs. 12.5%; P <.001).
Major secondary endpoints, such as ORR (67.2% vs. 20.3%), complete response rate (15.6% vs. 1.6%; P =.0066), and progression-free survival (16.7 months vs. 3.5 months; hazard ratio [HR] 0.270, 95% CI: 0.169, 0.430; P <.001) were all highly statistically significant favoring the Adcetris group over the control group.
Adult Dosage:
Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. Untreated Stage III/IV (initiate G-CSF starting with Cycle 1): 1.2mg/kg up to max 120mg/dose every 2 weeks; continue until max 12 doses, disease progression or unacceptable toxicity. Untreated sALCL or PTCL: 1.8mg/kg up to max 180mg/dose every 3 weeks with each cycle of chemotherapy for 6–8 doses; for PTCL: initiate G-CSF starting with Cycle 1. Others: 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until disease progression or unacceptable toxicity. cHL consolidation: initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT; max 16 cycles. MF or pcALCL: max 16 cycles. Mild hepatic impairment (Child-Pugh A): (untreated Stage III/IV): 0.9mg/kg up to max 90mg every 2 weeks; (others): 1.2mg/kg up to 120mg every 3 weeks. Dose modifications: see full labeling.
Children Dosage:
<2yrs (high risk cHL) and <18yrs (all other indications): not established. Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. ≥2yrs: High risk cHL (initiate G-CSF starting with Cycle 1): 1.8mg/kg up to max 180mg every 3 weeks with each cycle of chemotherapy for max 5 doses. Mild hepatic impairment (Child-Pugh A): 1.2mg/kg up to 120mg every 3 weeks. Dose modifications: see full labeling.
ADCETRIS Contraindications:
Concomitant bleomycin.
Boxed Warning:
Progressive multifocal leukoencephalopathy (PML).
ADCETRIS Warnings/Precautions:
Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed. Monitor for neuropathy; delay, change dose, or discontinue if new or worsening symptoms occur. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for fever or Grade 3 or 4 neutropenia; delay, reduce, discontinue dose or consider G-CSF prophylaxis if develops. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Monitor for emergence of bacterial, fungal, or viral infections. Monitor for pulmonary toxicity; if symptoms occur, withhold dose during evaluation and until improvement. Monitor serum glucose; if hyperglycemia develops, treat as clinically indicated. Monitor liver enzymes and bilirubin; delay, change dose, or discontinue if hepatotoxicity occurs. Severe renal impairment (CrCl <30mL/min) or moderate or severe hepatic (Child-Pugh B/C) impairment: avoid. Discontinue if serious skin reactions (eg, SJS, TEN) occur. GI complications: evaluate and treat if new or worsening GI symptoms develop. Embryo-fetal toxicity. Advise females and males of reproductive potential to use effective contraception during and for ≥6 months after final dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended.
ADCETRIS Classification:
CD30-directed antibody-drug conjugate.
ADCETRIS Interactions:
See Contraindications. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole); monitor closely. May be antagonized by potent CYP3A4 inducers (eg, rifampin).
Adverse Reactions:
Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper RTI, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, febrile neutropenia.
Drug Elimination:
ADC elimination exhibited a multi-exponential decline with a half-life of ~4 to 6 days. MMAE elimination exhibited a mono-exponential decline with a half-life of ~3 to 4 days. Elimination of MMAE appeared to be limited by its rate of release from ADC.
After a single dose of 1.8 mg/kg of Adcetris in patients, ~24% of the total MMAE administered was recovered in both urine and feces over a 1-week period, ~72% of which was recovered in the feces, and the majority was excreted unchanged.
Generic Drug Availability:
NO
How Supplied:
Single-use vial—1
