ADCETRIS® (brentuximab vedotin)

Therapeutic indication

Adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL)

Mechanism of action

Brentuximab vedotin is an antibody drug conjugate (ADC) that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumour cells. Nonclinical data suggest that the biological activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within the cell, a single defined active species, MMAE, is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell. Classical HL and sALCL express CD30 as an antigen on the surface of their malignant cells. This expression is independent of disease stage, line of therapy or transplant status. These features make CD30 a target for therapeutic intervention. Because of the CD30-targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistance as CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy, irrespective of prior transplant status. The CD30-targeted mechanism of action of brentuximab vedotin, the consistent expression of CD30 throughout the classical HL and sALCL disease and therapeutic spectrums and clinical evidence in two CD30-positive malignancies following multiple lines of treatment provide a biologic rationale for its use in patients with relapsed and refractory classical HL and sALCL with or without prior ASCT. Contributions to the mechanism of action by other antibody associated functions have not been excluded.

Therapeutic indication

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

1. following autologous stem cell transplant (ASCT) or

2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT.

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

Reimbursement modalities

ADCETRIS is reimbursed for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

1. following autologous stem cell transplant (ASCT) or

2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

ADCETRIS is reimbursed for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

§ 7280000 , chapter IV (21th of December 2001), paper version available on National Institute for Disability Health Insurance website

1,8 mg, Q3W

The maximum number of reimbursable cycles is limited to 16 in total.

Administration and dosage

Brentuximab vedotin should be administered under the supervision of a physician experienced in the use of anti-cancer agents.

Posology

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.

The recommended starting dose for the retreatment of patients with relapsed or refractory HL or sALCL who have previously responded to treatment with ADCETRIS is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose.

Dose modifications

Toxicity

General

If the patient’s weight is more than 100 kg, the dose calculation should use 100 kg.

Complete blood counts should be monitored prior to administration of each dose of this treatment.

Patients should be monitored during and after infusion.

Treatment should be continued until disease progression or unacceptable toxicity.

Patients with relapsed or refractory HL or sALCL who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately 1 year).

For patients with HL at increased risk of relapse or progression following ASCT, ADCETRIS treatment should start following recovery from ASCT based on clinical judgment. These patients should receive up to 16 cycles.

Neutropenia

If neutropenia develops during treatment it should be managed by dose delays. See Table 1 below for appropriate dosing recommendations

Table 1: Dosing recommendations for neutropenia

Severity grade of neutropenia (signs and symptoms [abbreviated description of CTCAE^a])	Modification of dosing schedule
Grade 1 (3 9/L) or Grade 2 (<1500 - 1000/mm³ <1.5 – 1.0 x 10⁹/L)	Continue with the same dose and schedule
Grade 3 (<1,000 – 500/mm³ <1.0 – 0.5 x 10⁹/L) or Grade 4 (<500/mm³ <0.5 x 10⁹/L)	Withhold dose until toxicity returns to ≤ Grade 2 or baseline then resume treatment at the same dose and schedule ^b. Consider growth factor support (G-CSF or GM-CSF) in subsequent cycles for patients who develop Grade 3 or Grade 4 neutropenia.

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; see Neutrophils/granulocytes; LLN= lower limit of normal

b. Patients who develop Grade 3 or Grade 4 lymphopenia may continue treatment without interruption.

Peripheral neuropathy

If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 2 below for appropriate dosing recommendations.

Table 2: Dosing recommendations for new or worsening peripheral sensory or motor neuropathy

Severity of peripheral sensory or motor neuropathy (signs and symptoms [abbreviated description of CTCAE^a])	Modification of dose and schedule
Grade 1 (paraesthesia and/or loss of reflexes, with no loss of function)	Withhold dose until toxicity returns to ≤ Grade 1 or baseline, then restart treatment at a reduced dose of 1.2 mg/kg every 3 weeks
Grade 2 (interfering with function but not with activities of daily living) or Grade 3 (interfering with activities of daily living)	Withhold dose until toxicity returns to ≤ Grade 1 or baseline, then restart treatment at a reduced dose of 1.2 mg/kg every 3 weeks
Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life threatening or leads to paralysis)	Discontinue treatment

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; see neuropathy: motor; neuropathy: sensory; and neuropathic pain.

Hepatic impairment

The recommended starting dose in patients with hepatic impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with hepatic impairment should be closely monitored for adverse events.

Renal impairment

The recommended starting dose in patients with severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal impairment should be closely monitored for adverse events.

Drug-drug interactions

Interaction with medicinal products metabolized through CYP3A4 route (CYP3A4 inhibitors/inducers)

Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Table 1: Dosing recommendations for neutropenia.

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin. Though PK data are limited, co administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed.

Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure to medicines that are metabolized by CYP3A4 enzymes.

Drug-food interactions

Sodium content in excipients

This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Adverse events of special interest

Summary of the safety profile

The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date. Frequencies of adverse reactions described below and in Table 3 have been determined based on data generated from clinical studies.

In the pooled dataset of ADCETRIS as monotherapy across HL, sALCL and CTCL studies (SG035-0003, SG035-0004, SGN35-005, SGN35-006, C25001 and C25007) the most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.

Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%.

Adverse events led to treatment discontinuation in 24% of patients receiving brentuximab vedotin.

The safety data in patients retreated with ADCETRIS (SGN35-006) were consistent with those observed in the combined pivotal phase 2 studies, with the exception of peripheral motor neuropathy, which had a higher incidence (28% vs. 9% in the pivotal phase 2 studies) and was primarily Grade 2. Patients also had a higher incidence of arthralgia, Grade 3 anaemia, and back pain compared to patients observed in the combined pivotal phase 2 studies.

The safety data in patients with relapsed or refractory HL who had not received an autologous stem cell transplant and were treated with the recommended dose of 1.8 mg/kg every three weeks in a single-arm phase 4 study (n=60), the phase 1 dose escalation and clinical pharmacology studies (n=15 patients) and in the NPP (n=26 patients) were consistent with the safety profile of the pivotal clinical studies.

Tabulated list of adverse reactions

Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 3). Within each System Organ Class, adverse reactions are listed under frequency categories of: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3: Adverse reactions to ADCETRIS

System organ class
Infections and infestations
Very common:	Infection^a, upper respiratory tract infection
Common:	Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex
Uncommon:	Oral candidiasis, Pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, cytomegalovirus infection or reactivation
Frequency not known:	Progressive multifocal leukoencephalopathy
Blood and lymphatic system disorders
Very common:	Neutropenia
Common:	Anaemia, thrombocytopenia
Frequency not known:	Febrile neutropenia
Immune system disorders
Frequency not known:	Anaphylactic reaction
Metabolism and nutrition disorders
Common :	Hyperglycaemia
Uncommon:	Tumour lysis syndrome
Nervous system disorders
Very common:	Peripheral sensory neuropathy, peripheral motor neuropathy
Common:	Dizziness, demyelinating polyneuropathy
Respiratory, thoracic and mediastinal disorders
Very Common:	Cough, dyspnoea
Gastro-intestinal disorders
Very common:	Diarrhoea, nausea, vomiting, constipation, abdominal pain
Uncommon:	Pancreatitis acute
Hepatobiliary disorders
Common:	Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased
Skin and subcutaneous tissue disorders
Very common:	Alopecia, pruritus
Common:	Rash
Rare:	Stevens-Johnson syndrome/toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Very common:	Myalgia, arthralgia
Common:	Back pain
General disorders and administration site conditions
Very common:	Fatigue, chills, pyrexia, infusion-related reactions^b
Investigations
Very common:	Weight decreased

a. Preferred terms that were reported under the Infections and Infestations SOC include sepsis/septic shock, upper respiratory tract infection, herpes zoster, and pneumonia.

b. Preferred terms associated with IRRs were headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough.

Management of adverse events

Progressive multifocal leukoencephalopathy

Pancreatitis

Pulmonary Toxicity

Tumour lysis syndrome

Peripheral neuropathy

Febrile neutropenia

Stevens-Johnson syndrome and toxic epidermal necrolysis

Gastrointestinal Complications

Hepatotoxicity

Hyperglycaemia

For more information about the management of adverse events, please see the SUMMARY OF PRODUCT CHARACTERISTICS.

Sodium content in excipients

This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Initial work-up before start of treatment

Premedication may include paracetamol, an antihistamine and a corticosteroid.

Concomitant Treatment

Nihil

Response evaluation

Treatment should be continued until disease progression or unacceptable toxicity.

Patients with relapsed or refractory HL or sALCL who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately 1 year)

Full SmPC:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002455/WC500135055.pdf