Adcetris

Adcetris Mechanism of Action

brentuximab vedotin

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Action
Pharmacologic class: CD30-directed antibody‚Äźdrug conjugate. Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents; monoclonal antibodies. ATC code: L01XC12.
Pharmacology: Pharmacodynamics: Mechanism of action: ADCETRIS 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 ADCETRIS 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 ADCETRIS 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 ADCETRIS, 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.
Pharmacodynamic effects: Cardiac electrophysiology: Forty-six (46) patients with CD30-expressing hematologic malignancies were evaluable of the 52 patients who received 1.8 mg/kg of ADCETRIS every 3 weeks as part of a phase 1, single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate the effect of ADCETRIS on cardiac ventricular re-polarization and the predefined primary analysis was the change in QTc from baseline to multiple time points in Cycle 1.
The upper 90% confidence interval (CI) around the mean effect on QTc was <10 msec at each of the Cycle 1 and Cycle 3 post-baseline time points. These data indicate the absence of clinically relevant QT prolongation due to ADCETRIS administered at a dose of 1.8 mg/kg every 3 weeks in patients with CD30-expressing malignancies.
Clinical efficacy: Hodgkin lymphoma: Study C25003: The efficacy and safety of ADCETRIS were evaluated in a randomized, open-label, 2-arm, multicentre trial in 1334 patients with previously untreated advanced classical (cHL) in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]). All patients had CD30-expressing cHL. Sixty-two percent of patients had extranodal site involvement. Of the 1334 patients, 664 patients were randomized to the ADCETRIS + AVD arm and 670 patients were randomized to the ABVD (doxorubicin [A], bleomycin [B], vinblastine [V] and dacarbazine [D]) arm and stratified by the number of International Prognostic Factor Project (IPFP) risk factors and region. Patients were treated with 1.2 mg/kg of ADCETRIS administered as an intravenous infusion over 30 minutes on days 1 and 15 of each 28-day cycle + doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2. The median number of cycles received was 6 (range, 1 to 6 cycles).
In the ADCETRIS + AVD arm: patients had Stage III (36%) or IV disease (64%), and 62% had extranodal involvement at diagnosis. Most patients were male (57%) and white (84%). The median age was 35 years (range, 18-82); 84 patients (13%) were 60 years or older.
These and other demographics/baseline characteristics were well balanced between the 2 treatment arms.
The primary endpoint in Study C25003 was modified PFS (mPFS) per IRF, defined as time from randomization to progression, death, or evidence of non-complete response (non-CR) after completion of frontline therapy per independent review facility (IRF) followed by subsequent anticancer therapy. The median mPFS by IRF assessment was not estimable for either treatment arm. The results showed a statistically significant improvement in modified PFS for ADCETRIS +AVD, with a 2-sided p-value of 0.035 based on a stratified log-rank test. The stratified hazard ratio was 0.770 (95% CI, 0.603; 0.983), indicating a 23% reduction in the risk of modified PFS events for ADCETRIS +AVD versus ABVD. Table 1 provides the efficacy results for modified PFS. (See Table 1.)

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Pre-specified subgroup analyses of modified PFS per IRF were performed. The analyses showed that efficacy trended consistently in favor of patients who received ADCETRIS + AVD compared with patients who received ABVD for most subgroups, as summarized in Figure 1. (See Figure 1.)

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Study SGN35-005: The efficacy and safety of ADCETRIS were evaluated in a randomized, double-blind, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT. Patients with known cerebral/meningeal disease, including history of PML were excluded from the study. See Table 2 for patient characteristics. Of the 329 patients, 165 patients were randomized to the treatment arm and 164 patients were randomized to the placebo arm. In the study, patients were to receive their first dose after recovery from ASCT (between days 30-45 following ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over 30 minutes every 3 weeks for up to 16 cycles.
Eligible patients were required to have at least one of the following risk factors: HL that was refractory to frontline treatment; Relapsed or progressive HL that occurred <12 months from the end of frontline treatment; Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodal masses into adjacent vital organs. (See Table 2.)

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The efficacy results are shown in Table 3. The primary endpoint of PFS was met and showed a difference in median PFS of 18.8 months in favour of the treatment arm. (See Table 3.)

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Pre-specified subgroup analyses of PFS per IRF were performed by patients' best response to pre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PET status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. The analyses showed a consistent trend towards benefit for patients who received ADCETRIS compared with patients who received placebo with the exception of patients ≥65 years of age (n=8).
No differences were observed in quality of life between the treatment and placebo arms. Medical resource utilization (MRU) analysis showed that hospitalizations and outpatient visits, as well as working days/other activities missed by patients and caregivers were lower with ADCETRIS compared with placebo in patients with HL at increased risk of relapse.
An updated analysis conducted after 3 years of follow-up showed a sustained PFS improvement per IRF (HR = 0.58 [95% CI (0.41, 0.81)]).
Post-hoc Risk Factor Analyses: Post-hoc analyses were performed to evaluate the impact of increased risk (number of risk factors) on clinical benefit (Table 4). Representative risk factors for these analyses were: HL that occurred <12 months or HL that was refractory to frontline therapy; Best response of PR or SD to most recent salvage therapy as determined by CT and/or PET scanning; Extranodal disease at pre-ASCT relapse; B symptoms at pre-ASCT relapse; Two or more prior salvage therapies.
The results of these post-hoc analyses suggest increased clinical benefit for patients with two or more risk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or OS has been observed in patients with one risk factor for relapse or progression. (See Table 4.)

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At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, the hazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS per investigator was 0.41 (95% CI [0.29, 0.58]) (see Figures 2 and 3).

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Study SG035-0003: The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal open label, single-arm, multicenter study in 102 patients with relapsed or refractory HL. See Table 5 as follows for a summary of baseline patient and disease characteristics. (See Table 5.)

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Eighteen (18) patients (18%) received 16 cycles of ADCETRIS; and the median number of cycles received was 9 (ranging from 1 to 16).
Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response assessments were performed at cycles 2, 4, 7, 10, 13, and 16 with PET at cycles 4 and 7.
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 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, 8 responding patients went on to receive an allogeneic SCT. For further efficacy results (see Table 6).

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An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with ADCETRIS as part of the SG035-0003 clinical studies, experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.
Of the 35 patients (33%) who had B symptoms at baseline, 27 patients (77%) experienced resolution of all B symptoms at a median time of 0.7 months from initiation of ADCETRIS.
Data were collected from patients (n=15) in phase 1 dose escalation and clinical pharmacology studies, and from patients (n=26) in a NPP, with relapsed or refractory HL who had not received an ASCT, and who were treated with 1.8 mg/kg of ADCETRIS every 3 weeks.
Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 3 with a range of 1 to 7) before first administration with ADCETRIS. Fifty nine percent (59%) of patients had advanced stage disease (stage III or IV) at initial diagnosis.
Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after a median of 5 cycles of ADCETRIS.
Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates: Study C25007: A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n=60) who had received at least one prior chemotherapeutic regimen and at the time of treatment initiation with ADCETRIS were not considered candidates for SCT or multiagent chemotherapy. The median number of cycles was 7 (range 1 to 16 cycles). Patients were treated with 1.8 mg/kg of ADCETRIS every 3 weeks. Per IRF, the overall response rate (ORR) in the ITT population was 50% (95% CI, 37; 63%). A best overall response of CR was reported for 7 patients (12%); PR was reported for 23 patients (38%). Twenty eight patients (47%) went on to receive SCT after a median of 7 cycles (range 4 to 16 cycles) of ADCETRIS treatment. The 32 patients (53%) who did not receive subsequent SCT also received ADCETRIS for a median of 7 cycles (range 1 to 16 cycles). Eleven patients (18%) had received one prior chemotherapeutic regimen. Per IRF, the overall response rate (ORR) in these patients was 45% (95% CI, 17; 77%). A best overall response of CR was reported for 1 patient (9%); PR was reported for 4 patients (36%).
Data were also collected from patients (n=15) in phase 1 dose escalation and clinical pharmacology studies, and from patients (n=26) in a Named Patient Program (NPP), with relapsed or refractory HL who had not received an ASCT, and who were treated with 1.8 mg/kg of ADCETRIS every 3 weeks.
Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 3 with a range of 1 to 7) before first administration with ADCETRIS. Fifty nine percent (59%) of patients had advanced stage disease (stage III or IV) at initial diagnosis.
Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after a median of 5 cycles of ADCETRIS.
Study SGN35-006 (Retreatment Study): The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed or refractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 7 (range, 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%) achieved a CR and 6 patients (30%) achieved a PR with ADCETRIS retreatment, for an ORR of 60%. The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and CR, respectively.
Peripheral T-Cell lymphoma: Study SGN35-014: The efficacy and safety of ADCETRIS were evaluated in a randomized, double-blind, double-dummy, active-controlled, multicenter trial of 452 patients with previously untreated PTCL in combination with cyclophosphamide [C], doxorubicin [H], and prednisone [P] (CHP). Of the 452 patients, 226 were randomized to treatment with ADCETRIS + CHP and 226 patients were randomized to treatment with CHOP (cyclophosphamide [C], doxorubicin [H], vincristine [O], and prednisone [P]). Randomization was stratified by ALK-positive sALCL versus all other subtypes and by the International Prognostic Index (IPI) score. Patients were treated with ADCETRIS administered as an intravenous infusion over 30 minutes on Day 1 of each 21-day cycle for 6 to 8 cycles + CHP. The median number of cycles received was 6 (range, 1 to 8 cycles); 70% of patients received 6 cycles of treatment, and 18% received 8 cycles of treatment. Table 7 provides a summary of baseline patient and disease characteristics. (See Table 7.)

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The primary endpoint in SGN35-014 was PFS per IRF, defined as the time from the date of randomization to the date of first documentation of progressive disease, death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease, whichever occurs first.
Receipt of post-treatment consolidative radiotherapy, post-treatment chemotherapy for the purpose of mobilizing peripheral blood stem cells, or consolidative autologous or allogeneic stem cell transplant were not considered as disease progression or as having started new anticancer therapy.
Upon establishing statistical significance of PFS per IRF, the key secondary endpoints, PFS per IRF for subjects with centrally-confirmed sALCL, CR rate per IRF following the completion of study treatment, OS, and ORR per IRF following the completion of study treatment, were tested by a fixed sequence testing procedure.
The primary endpoint and alpha-protected, key secondary endpoints, which were evaluated hierarchically, were met. The median PFS per IRF was 48.2 months on the ADCETRIS + CHP arm versus 20.8 months on the CHOP arm. The stratified hazard ratio was 0.71 (95% CI: 0.54, 0.93, P=0.011), indicating a 29% reduction in the risk of PFS events for ADCETRIS + CHP versus CHOP (see Table 8 and Figures 4 and 5).

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Of the 452 patients, 72 patients had PTCL-NOS; 29 were randomized to treatment with ADCETRIS + CHP and 43 patients were randomized to treatment with CHOP. The median PFS per IRF was 21.2 months in the ADCETRIS + CHP arm versus 11.4 months in the CHOP arm. The stratified hazard ratio was 0.75 (95% CI: 0.41, 1.37).
54 patients had AITL; 30 were randomized to treatment with ADCETRIS + CHP and 24 patients were randomized to treatment with CHOP. The median PFS per IRF was 13.9 months in the ADCETRIS + CHP arm versus 47.57 months in the CHOP arm. The stratified hazard ratio was 1.40 (95% CI: 0.64, 3.07). For overall survival, the stratified hazard ratio was 0.87 (95% CI: 0.29; 2.58). The median OS was not reached in either arm.
The European Organization for Research and Treatment of Cancer Quality of Life 30-item Questionnaire (EORTC-QLQ-C30) showed no clinically meaningful difference between the two treatment arms.
Medical resource utilization (MRU) was assessed from healthcare data collected from Cycle 1 through long-term follow-up. The hospitalization visit rate was lower in subjects who received A+CHP compared to subjects who received CHOP, but there was no meaningful difference in the median number of hospitalization visits between the arms.
Systemic anaplastic large cell lymphoma: Study SG035-0004: The efficacy and safety of ADCETRIS as a single agent was evaluated in an open-label, single-arm, multicenter study in 58 patients with relapsed or refractory sALCL.
See Table 9 as follows for a summary of baseline patient and disease characteristics. (See Table 9.)

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The median time from initial sALCL diagnosis to first dose with ADCETRIS was 16.8 months.
Ten (10) patients (17%) received 16 cycles of ADCETRIS; the median number of cycles received was 7 (range, 1 to 16).
Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response assessments were performed at cycles 2, 4, 7, 10, 13 and 16 with PET at cycles 4 and 7.
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 was achieved in 97% of patients. The estimated overall survival at 5 years was 60%. The median observation time (time to death or last contact) from first dose was 71.4 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 9 responding patients went on to autologous SCT. For further efficacy results, (see Table 10).

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An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treated with ADCETRIS as part of the SG035-0004 clinical studies, experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.
Of the 17 patients (29%) who had B symptoms at baseline, 14 patients (82%) experienced resolution of all B symptoms in a median time from initiation of ADCETRIS of 0.7 months.
Study SGN35-006 (Retreatment study): The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Seven patients with relapsed sALCL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 8.5 (range, 2 to 30 cycles). Of the 8 sALCL patients, 3 were retreated twice for a total of 11 retreatment experiences. Retreatment with ADCETRIS resulted in 6 CRs (55%) and 4 PRs (36%), for an ORR of 91%. The median duration of response was 8.8 and 12.3 months in patients who achieved OR (CR+PR) and CR, respectively.
Cutaneous T-Cell Lymphoma: Study C25001: The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal phase 3, open-label, randomized, multicenter 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 ADCETRIS 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 ADCETRIS 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 ADCETRIS 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. (See Table 11.)

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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. Table 12 includes the results for ORR4 and other key secondary endpoints. (See Table 12.)

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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 ADCETRIS compared with patients who received physician's choice. ORR4 was 50% and 75% in the ADCETRIS 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 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%.
Pharmacokinetics: The pharmacokinetics of ADCETRIS were evaluated in phase 1 studies and in a population pharmacokinetic analysis of data from 314 patients. In all clinical trials, ADCETRIS was administered as an intravenous infusion.
Monotherapy: The serum pharmacokinetics of ADC following an intravenous dose of ADCETRIS were similar to other antibody product.
Maximum concentrations of brentuximab vedotin ADC were typically observed at the end of infusion or the sampling timepoint closest to the end of infusion. A multiexponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 6 days. Exposures were approximately dose proportional. Minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule, consistent with the terminal half-life estimate. Typical Cmax and AUC of ADC after a single 1.8 mg/kg in a phase 1 study was approximately 31.98 μg/ml and 79.41 μg/ml x day respectively.
MMAE is the major metabolite of brentuximab vedotin. Median Cmax, AUC and Tmax 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 ADCETRIS 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.
In the first cycle, higher MMAE exposure was associated with an absolute decrease in neutrophil count.
Combination therapy: The pharmacokinetics of ADCETRIS in combination with AVD were evaluated in a single phase 3 study in 661 patients (C25003). Population pharmacokinetic analysis indicated that the pharmacokinetics of ADCETRIS in combination with AVD were consistent to that in monotherapy.
After multiple-dose, IV infusion of 1.2 mg/kg ADCETRIS every two weeks, maximal serum concentrations of ADC were observed near the end of the infusion and elimination exhibited a multi exponential decline with a t1/2z of approximately 4 to 5 days. Maximal plasma concentrations of MMAE were observed approximately 2 days after the end of infusion, and exhibited a mono-exponential decline with a t1/2z of approximately 3 to 4 days.
After multiple-dose, IV infusion of 1.2 mg/kg ADCETRIS every two weeks, steady-state trough concentrations of ADC and MMAE were achieved by Cycle 3. Once steady-state was achieved, the PK of ADC did not appear to change with time. ADC accumulation (as assessed by AUC14D between Cycle 1 and Cycle 3) was 1.27-fold. The exposure of MMAE (as assessed by AUC14D between Cycle 1 and Cycle 3) appeared to decrease with time by approximately 50%.
The pharmacokinetics of ADCETRIS in combination with CHP were evaluated in a single phase 3 study in 223 patients (SGN35-014). After multiple-dose IV infusion of 1.8 mg/kg ADCETRIS every 3 weeks, the pharmacokinetics of ADC and MMAE were similar to those of monotherapy.
Distribution: In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is not likely to displace or to be displaced by highly protein-bound medicines. In vitro, MMAE was a substrate of P-gp and was not an inhibitor of P-gp at clinical concentrations.
In humans, the mean steady state volume of distribution was approximately 6-10 l for ADC. Based on population PK estimation the typical apparent volume of distribution (VM and VMP) of MMAE were 7.37 l and 36.4 l respectively.
Metabolism: The ADC is expected to be catabolised as a protein with component amino acids recycled or eliminated.
In vivo data in animals and humans suggest that only a small fraction of MMAE released from ADCETRIS is metabolized. The levels of MMAE metabolites have not been measured in human plasma. At least one metabolite of MMAE has been shown to be active in vitro.
MMAE is a substrate of CYP3A4 and possibly CYP2D6. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits only CYP3A4/5 at concentrations much higher than was achieved during clinical application. MMAE does not inhibit other isoforms.
MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.
Elimination: The ADC is eliminated by catabolism with a typical estimated CL and half-life of 1.457 l/day and 4-6 days respectively.
The elimination of MMAE was limited by its rate of release from ADC, typical apparent CL and half-life of MMAE was 19.99 l/day and 3-4 days respectively.
An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of ADCETRIS.
Approximately 24% of the total MMAE administered as part of the ADC during a ADCETRIS infusion was recovered in both urine and faeces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the faeces. A lesser amount of MMAE (28%) was excreted in the urine.
Pharmacokinetics in special populations: Population PK analysis showed that baseline serum albumin concentration was a significant covariate of MMAE clearance. The analysis indicated that MMAE clearance was 2-fold lower in patients with low serum albumin concentrations <3.0 g/dl compared with patients with serum albumin concentrations within the normal range.
Hepatic impairment: A study evaluated the pharmacokinetics of ADCETRIS and MMAE after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n = 5) and severe (Child-Pugh C; n = 1) hepatic impairment. Compared to patients with normal hepatic function, MMAE exposure increased approximately 2.3-fold (90% CI 1.27 - 4.12 fold) in patients with hepatic impairment.
Renal impairment: A study evaluated the pharmacokinetics of ADCETRIS and MMAE after administration of 1.2 mg/kg of ADCETRIS to patients with mild (n=4), moderate (n=3) and severe (n=3) renal impairment. Compared to patients with normal renal function, MMAE exposure increased approximately 1.9-fold (90% CI 0.85 - 4.21 fold) in patients with severe renal impairment (creatinine clearance < 30 ml/min). No effect was observed in patients with mild or moderate renal impairment.
Elderly patients: The population pharmacokinetics of ADCETRIS were examined from several monotherapy studies, including data from 380 patients up to 87 years old (34 patients ≥ 65 <75 and 17 patients > 75 years of age). Additionally, the population pharmacokinetics of ADCETRIS in combination with AVD were examined, including data from 661 patients up to 82 years old (42 patients ≥65 < 75 and 17 patients ≥ 75 years of age). The influence of age on pharmacokinetics was investigated in each analysis and it was not a significant covariate. The safety profile in elderly patients with CTCL was consistent with that of adult patients, therefore dosing recommendations for patients aged 65 and older are the same for adults.
Paediatric population: The pharmacokinetics of ADC and MMAE following an intravenous dose of ADCETRIS were evaluated in a phase 1/2 study in 36 pediatric patients (age 7-17 years) with relapsed or refractory HL or sALCL (see Pharmacodynamics as previously mentioned). After multiple-dose IV infusion of 1.4 mg/kg or 1.8 mg/kg given every 3 weeks, the pharmacokinetic properties of ADC and MMAE were consistent with that of adults. With body-weight normalized dosing, exposure to ADC and MMAE in adolescents (age 12-17 years) appeared to be comparable with adult exposure, however, there was a trend observed for lower exposures in children (age 7-11 years) at lower body weights. Median ADC and MMAE exposures in adolescents were approximately 3% lower and 13% higher, respectively, whereas median ADC and MMAE exposures in children were approximately 14% and 53% lower, respectively, when compared to adult patients.
Toxicology: Preclinical safety data: MMAE has been shown to have aneugenic properties in an in vivo rat bone marrow micronucleus study. These results were consistent with the pharmacological effect of MMAE on the mitotic apparatus (disruption of the microtubule network) in cells.
The effects of ADCETRIS on human male and female fertility have not been studied.
However, results of repeat-dose toxicity studies in rats indicate the potential for ADCETRIS to impair male reproductive function and fertility. Testicular atrophy and degeneration were partially reversible following a 16-week treatment-free period.
ADCETRIS caused embryo-foetal lethality in pregnant female rats.
In nonclinical studies, lymphoid depletion and reduced thymic weight were observed, consistent with the pharmacologic disruption of microtubules caused by MMAE derived from ADCETRIS.
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