Change to section

Details of change

4.2     Posology and method of administration

The safety and efficacy of children less than 18 years have not yet been established. No data are available. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

4.8       Undesirable effects

There was a trend of increased clearance of brentuximab vedotin in paediatric patients confirmed positive for ADAs. No patients aged <12 years (0 of 11) and 2 patients aged ≥12 years (2 of 23) became persistently ADA positive.

Paediatric population

Safety was evaluated in a phase 1/2 study in paediatric patients aged 7-17 years of age (n=36) with relapsed or refractory (r/r) HL and sALCL (see section 5.1).  In this study in 36 patients, no new safety concerns were reported.

5.1       Pharmacodynamic properties

Paediatric Population

The safety, pharmacokinetics and anti-tumour activity of brentuximab vedotin in 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n=12 and adolescents aged 12 to 17 years, n=24) were evaluated in a phase 1/2 open-label, single-agent, multicentre dose-escalation study (C25002). Phase 1 of the study assessed the safety profile (see section 4.8), determined the paediatric maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and assessed the pharmacokinetics of brentuximab vedotin (see section 5.2). Phase 1 included 3 r/r HL patients treated at 1.4 mg/kg and 9 patients (7 r/r HL and 2 sALCL) treated at 1.8 mg/kg. The MTD was not reached. The RP2D was determined to be 1.8 mg/kg. Across the study, a total of 16 patients with r/r HL and 17 patients with r/r sALCL, of whom 10 were in first relapse, were treated with 1.8 mg/kg of brentuximab vedotin. The best overall response rate (ORR) per independent review facility (IRF) was analysed across both study phases at the RP2D. Of these 33 patients who received the RP2D, 32 were evaluable for response. The ORR was 47% in response-evaluable patients with r/r HL, 53% in patients with r/r sALCL and 60% in sALCL patients in first relapse. Eight HL patients and 9 sALCL patients went on to receive SCT following treatment with brentuximab vedotin.

5.2       Pharmacokinetic properties

The pharmacokinetics of brentuximab vedotin ADC and MMAE following a 30-minute intravenous infusion of BV administered at 1.4 mg/kg or 1.8 mg/kg given every 3 weeks were evaluated in a phase 1/2 clinical trial of 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n=12 and adolescents aged 12 to 17 years, n=24) (see section 5.1). The Cmax of ADC was typically observed at the end of infusion or the sampling closest to the end of infusion. A multi-exponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 5 days. Exposures were approximately dose proportional with a trend observed for lower ADC exposures at lower ages/ body weights in the study population.  Median ADC AUC in children and adolescents from this study was approx. 14% and 3% lower than in adult patients, respectively, while MMAE exposures were 53% lower and 13% higher, respectively, than in adult patients. Median Cmax and AUC of ADC after a single 1.8 mg/kg dose were 29.8 µg/mL and 67.9 µg*day/mL, respectively, in patients <12 years of age and 34.4 µg/mL and 77.8 µg*day/mL, respectively, in patients ≥12 years of age. Median Cmax, AUC, and Tmax of MMAE after a single 1.8 mg/kg dose were 3.73 ng/mL, 17.3 ng*day/mL, and 1.92 days, respectively, in patients <12 years of age and 6.33 ng/mL, 42.3 ng*day/mL, and 1.82 days, respectively, in patients ≥12 years of age. There was a trend of increased clearance of brentuximab vedotin in paediatric patients confirmed positive for ADAs. No patients aged <12 years (0 of 11) and 2 patients aged ≥12 years (2 of 23) became persistently ADA positive.

Clinical studies of brentuximab vedotin did not include sufficient numbers of patients below 18 years of age to determine whether the PK profile differs from adult patients.

10.       DATE OF REVISION OF THE TEXT

15 December 201711 January 2017

Change to section

Details of change

4.1     Therapeutic indications

Addition of the following:

ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy (see section 5.1).

4.2     Posology and method of administration

Addition of the following:

Patients with CTCL should receive up to 16 cycles (see section 5.1).

AND

The Based upon population PK analyses (see section 5.2) and the safety profile and efficacy in elderly patients, which are consistent with that of adult patients, the dosing recommendations for patients aged 65 and older have not been established. No data are the same as for adults.available. 

4.4       Special warnings and precautions for use

In the pivotal phase 2 (SG035-0003 and SG035-0004) population, the incidence of pre-existing peripheral neuropathy was 24%. Treatment emergent neuropathy occurred in 56% of the population. At the time of last evaluation, the majority of patients (83%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 17%, dose reductions were reported in 13%, and dose delays occurred in 21% of patients.

The incidence of pre-existing peripheral neuropathy in patients with relapsed or refractory HL or sALCL who were retreated with brentuximab vedotin was 48%. Treatment emergent neuropathy occurred in 69% of the population. At the time of last evaluation, the majority of patients who were retreated and experienced treatment-emergent peripheral neuropathy (80%) had improvement or resolution of their peripheral neuropathy symptoms. Peripheral neuropathy led to discontinuation in 21% and dose modifications in 34% of patients who were retreated.

4.8       Undesirable effects

Section 4.8 has been extensively updated

5.1       Pharmacodynamic properties

Classical HL,  and sALCL and subtypes of CTCL (including MF and pcALCL) 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 and CD30+ CTCL 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 and CD30+ CTCL after at least 1 prior systemic therapy.

AND

Cutaneous T-cell lymphoma

Study C25001

The efficacy and safety of brentuximab vedotin as a single agent was evaluated in a pivotal phase 3, open-label, randomised, multicentre study in 128 patients with histologically confirmed CD30+  CTCL. CD30 positivity was defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi staining pattern based on an immunohistochemistry assay (Ventana anti-CD30 [Ber-H2]). Patients with a diagnosis of mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL] were considered eligible for the study. Patients were stratified by these disease types and randomised 1:1 to receive either brentuximab vedotin or the physician’s choice of either methotrexate or bexarotene. Patients with pcALCL received either prior radiation therapy or at least 1 prior systemic therapy and patients with MF received at least 1 prior systemic therapy. Patients with a concurrent diagnosis of systemic ALCL, Sezary syndrome and other non-Hodgkin lymphoma (except for lymphomatoid papulosis [LyP]) were excluded from this study. Patients were treated with 1.8 mg/kg of brentuximab vedotin intravenously over 30 minutes every 3 weeks for up to 16 cycles or physician’s choice for up to 48 weeks. The median number of cycles was approximately 12 cycles in the brentuximab vedotin arm. In the physician’s choice arm, the median duration of treatment (number of cycles) for patients receiving bexarotene was approximately 16 weeks (5.5 cycles) and 11 weeks (3 cycles) for patients receiving methotrexate. Table 11 provides a summary of the baseline patient and disease characteristics.

Table 11: Summary of Baseline Patient and Disease Characteristics in the Phase 3 CTCL Study (ITT Population)

Patient characteristics    Brentuximab vedotin

N = 64   Physician’s Choice (Methotrexate or Bexarotene)

N= 64

Median age (range)        62 years (22-83)                58.5 years (22-83)

Patients ≥ 65 years old n (%)

Gender n (%)     28 (44%)

33M (52%)/31F (48%)     24 (38%)

37M (58%)/27F (42%)

ECOG status n (%)                          

0              43 (67)  46 (72)

1

2              18 (28)

3 (5)       16 (25)

2 (3)

Disease characteristics                  

Median number of prior therapies (range)           4 (0-13) 3.5 (1-15)

Median number of skin-directed therapies (range)          1 (0-6)   1 (0-9)

Median number of systemic therapies (range)   2 (0-11) 2 (1-8)

MF, n(%)             48 (75)  49 (77)

Early (IA-IIA)      15 (31)  18 (37)

Advanced (IIB-IVBa)       32 (67)  30 (61)

pcALCL, n(%)      16 (25)  15 (23)

Skin only              9 (56)     11 (73)

Extracutaneous disease                7 (44)     4 (27)

a One patient in each arm had incomplete staging data and are not included in the table

                The most common prior skin directed therapies in the ITT population were radiotherapy (64%), phototherapy (48%) and topical steroids (17%). The most common prior systemic therapies in the ITT population were chemotherapy (71%), immunotherapy (43%) and bexarotene (38%).

                The primary endpoint was objective response rate that lasts at least 4 months (ORR4) (duration from first response to last response ≥ 4 months), as determined by an independent review of the Global Response Score (GRS) consisting of skin evaluations (modified severity weighted assessment tool [mSWAT] as assessed per investigator), nodal and visceral radiographic assessment, and detection of circulating Sézary cells (Olsen 2011). Table 12 includes the results for ORR4 and other key secondary endpoints.

Table 12: Efficacy Results in CTCL Patients Treated with 1.8 mg/kg of Brentuximab Vedotin Every 3 Weeks (ITT Population)

                Brentuximab vedotin      (N=64)                 Physician’s Choice (Methatrexate or Bexarotene)

N=64

Objective Response Rate lasting at least 4 months (ORR4) per IRF

N (%)

Percent Difference (95% CI)        36 (56.3)              

43.8 (29.1, 58.4)                8 (12.5)

p-value                 <0.001  

Complete Response (CR) per IRF

N (%)

Percent Difference (95% CI)        10 (15.6)              

14.1 (-4.0, 31.5) 1 (1.6)

Adjusted p-valuea                           0.0046  

Progression Free Survival (PFS) per IRF

Median (months)            16.7                        3.5

Hazard Ratio                       0.270    

95% CI                   (0.17, 0.43)         

Adjusted p-valuea                           <0.001  

a   Calculated from a weighted Holm’s procedure

                Pre-specified subgroup analyses of ORR4 per IRF were performed by patients’ CTCL subtype, physicians’ choice of treatment, baseline ECOG status, age, gender, and geographic region. The analyses showed a consistent trend towards benefit for patients who received brentuximab vedotin compared with patients who received physician’s choice. ORR4 was 50% and 75% in the brentuximab vedotin arm versus 10.2% and 20% in the physician’s choice arm for MF and pcALCL, respectively.

No meaningful differences in quality of life (assessed by the EuroQol five dimensions questionnaire [EQ-5D] and Functional Assessment of Cancer Therapy-General [FACT-G]) were observed between the treatment arms.

The efficacy and safety of ADCETRIS were evaluated in two additional open-label studies in 108 patients with relapsed CD30+ CTCL (including patients with MF and pcALCL as well as SS, Lyp and mixed CTCL histology) regardless of CD30 expression level. Patients were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles.  The safety and efficacy results in these studies were consistent with results in Study C25001.  Overall response rates for MF were 54-66%; pcALCL, 67%; SS, 50%; LyP, 92%; and mixed CTCL histology, 82-85%. 

5.2       Pharmacokinetic properties

The population pharmacokinetics of brentuximab vedotin were examined from several studies, including data from 380 patients up to 87 years old (34 patients ≥65-<75 and 17 patients ≥75 years of age). The influence of age on pharmacokinetics was investigated and it was not a significant covariate (see section 4.2).

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 25 October 2012

Date of renewal: 21 October 2016 10 November 2017

10.       DATE OF REVISION OF THE TEXT

15 December 2017

Section

Details of change

5.1 Pharmacodynamic properties

In the section ‘Study SG035-0004’ the following text in red has been added:

The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of 58 patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. The estimated 36 month overall survival at 5 years was 63% (60% (95% CI [47%,73%]). The median observation time (time to death or last contact) from first dose was 3371.4 months).. The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 9 responding patients went on to receive an allogeneic stem cell transplant (SCT) and 7 9 responding patients went on to autologous SCT. For further efficacy results, see Table 10 and Figure 3.

In table 10 the following text in red has been added:

^{a.         The range of DOR was 0.1+ months to 21.739.1+ months and the median follow‑up time from first dose for patients who achieved objective response (OR) per IRF was 11.815.5 months.}

^{b.        Not estimable.}

^{a.            The estimated 36 month overall survival was 63% (the median observation time (time to death or last contact) from first dose was 33.4 months).}

The following Kaplan-Meier plot has been added:

Figure 3: Kaplan-Meier Plot of OS

10.  DATE OF REVISION OF THE TEXT

Updated as follows:

28 June 2016

22 June 2017

Change to section

Details of change

6.3 Shelf life

Increase of shelf-life of Adcetris from 3 years to 4 years.

10.  Date of revision of the text

28 June 2016

Change to section

Details of change

4.1       Therapeutic indications

Addition of following text in red   :

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT (see section 5.1).

4.2       Posology and method of administration

Addition of text in red:

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) (see section 5.1).

4.4       Special warnings and precautions for use

Addition of text in red:

In the phase 3 population, at the time of last evaluation, the majority of patients in the brentuximab vedotin arm (85%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 23%, dose reductions were reported in 29%, and dose delays occurred in 22% of patients.

4.8       Undesirable effects

Section 4.8 (Undesirable effects) has been extensively updated to include safety data from phase 2 and phase 3 studies.

5.1 Pharmacodynamic properties

Section 5.1( Pharmacodynamic properties) has been extensively updated to include Data from Study SGN35-005 which evaluated the efficacy and safety of brentuximab vedotin in a randomized, double-blind, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT.  Text, tables and Kaplan-Meier plots have been added.

 

10. Date of revision of the text

24 June 2016

Section

Update

4.4 Special warnings and precautions for use

Pulmonary Toxicity

Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving brentuximab vedotin.

Although a causal association with brentuximab vedotin has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding brentuximab vedotin dosing during evaluation and until symptomatic improvement.

4.4 Special warnings and precautions for use

Peripheral neuropathy

Brentuximab vedotin treatment may cause peripheral neuropathy, both sensory and motor. Brentuximab vedotin-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases.

In the pivotal phase 2 (SG035-0003 and SG035-0004) population, the incidence of pre-existing peripheral neuropathy was 24%. Treatment emergent neuropathy occurred in 56% of the population. At the time of last evaluation, the majority of patients (83%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 17%, dose reductions were reported in 13%, and dose delays occurred in 21% of patients.

4.4 Special warnings and precautions for use

Gastrointestinal Complications

Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with brentuximab vedotin. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Hepatotoxicity

Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been reported with brentuximab vedotin. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Liver function should be tested before initiating the treatment and routinely monitored in patients receiving brentuximab vedotin. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of brentuximab vedotin.

4.5 Interaction with other medicinal products and other forms of interaction

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin.: however it reduced exposure to MMAE by approximately 31%. Though PK data are limited, co administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed.

4.8 Undesirable effects

Serious infections and opportunistic infections have been reported in patients treated with this medicine (see section 4.4). In the pivotal phase 2 population, 17% of patients reported an event term that referred to an infection.

Serious adverse drug reactions in the pivotal phase 2 population were: neutropenia, thrombocytopenia, constipation, diarrhoea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycaemia, demyelinating polyneuropathy, tumour lysis syndrome and Stevens-Johnson syndrome.

The most frequently observed adverse reactions in the pivotal phase 2 population were: peripheral sensory neuropathy, fatigue, nausea, diarrhoea, diarrhoea, neutropenia, pyrexia, upper respiratory tract infection, neutropenia, and vomiting.

In the pivotal phase 2 population, adverse reactions led to treatment discontinuation in 23% of patients receiving brentuximab vedotin. Adverse reactions that led to treatment discontinuation in two or more HL or sALCL patients were peripheral sensory neuropathy (8%), peripheral motor neuropathy (2%), demyelinating polyneuropathy (2%), and recurrent Hodgkin’s disease (2%).

4.8 Undesirable effects

Description of selected adverse reactions

Adverse reactions that led to dose delays of up to 3 weeks in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (13%) (see section 4.2).

The adverse reaction that led to a dose reduction in more than 5% of patients was peripheral sensory neuropathy (9%). Eighty-nine percent (89%) of patients in the phase 2 studies remained at the recommended dose of 1.8 mg/kg while on treatment.

Severe and prolonged (≥1 week) neutropenia can occur with this treatment which may increase the risk of patients developing serious infections. The median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted ≥7 days. Less than half of the patients in the pivotal phase 2 population with Grade 3 or Grade 4 neutropenia had temporally associated infections, and the majority of temporally associated infections were Grade 1 or Grade 2.

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 48.9 weeks. At the time of last evaluation, 83% of the 89 patients who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement for all events was 16 weeks (range from 0.3 weeks to 106.6 weeks).

4.8 Undesirable effects

The presence of antibodies to brentuximab vedotin did not correlate with a clinically meaningful reduction in serum brentuximab vedotin levels and did not result in a decrease in the efficacy of brentuximab vedotin. While the presence of antibodies to brentuximab vedotin does not necessarily predict the development of an IRR, there was a higher incidence of IRRs observed in patients with persistently positive ATA (27%) relative to patients with transiently positive ATA (12%) and never positive ATA (7%).

5.2 Pharmacokinetic properties

MMAE is the major metabolite of brentuximab vedotin. Median C_max, AUC and T_max of MMAE after a single 1.8 mg/kg of the ADC in a phase 1 study was approximately 4.97 ng/ml, 37.03 ng/ml x day and 2.09 days respectively. MMAE exposures decreased after multiple doses of brentuximab vedotin with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses. MMAE is further metabolized mainly to an equally potent metabolite; however, its exposure is an order of magnitude lower than that of MMAE. Thus, it is not likely to have any substantial contribution to the systemic effects of MMAE.

10. DATE OF REVISION OF THE TEXT

28 April 2016

Change to section

Details of change

5.1 Pharmacodynamic properties

Tracked changes shown below:

Clinical efficacy

Hodgkin Lymphoma

Study SG035-0003

…

The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in the intent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission (CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months (the median observation time (time to death or last contact) from first dose was 32.7 months).35.1 months (range 1.8 to 72.9+ months). The estimated overall survival rate at 5 years was 41% (95% CI [31%, 51%]). The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 78 responding patients went on to receive an allogeneic SCT. For further efficacy results see Table 5.

Table 5: Efficacy results in relapsed or refractory Hodgkin lymphoma patients treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks

^{a.         The range of DOR was1was 1.2+ months to 26.143+ months and the median follow-up time from first dose for patients who achieved objective response (OR) per IRF was 9.0 months.}

^{b.        Not estimable.}

10. Date of revision of the text

Updated:

1^st April 2016

Uncommon Rare:

Stevens-Johnson syndrome/toxic epidermal necrolysis