July 1, 2016
Recommended Topic Related To:

Adcetris

"Nov. 4, 2014 -- Twenty-year-old Milton Wright III's life seemed to finally be on track. After a lifetime of interruptions to his education, his football career, and his plans to join the Marines, he found his way. He had launched a modeling caree"...

A A A

Adcetris




CLINICAL PHARMACOLOGY

Mechanism Of Action

Brentuximab vedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule disrupting agent. MMAE is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of ADCETRIS is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.

Pharmacodynamics

QT/QTc Prolongation Potential

The effect of brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an open-label, single-arm study in 46 evaluable patients with CD30-expressing hematologic malignancies. Administration of brentuximab vedotin did not prolong the mean QTc interval > 10 ms from baseline. Small increases in the mean QTc interval ( < 10 ms) cannot be excluded because this study did not include a placebo arm and a positive control arm.

Pharmacokinetics

The pharmacokinetics of brentuximab vedotin were evaluated in early development trials, including dose-finding trials, and in a population pharmacokinetic analysis of data from 314 patients. The pharmacokinetics of three analytes were determined: the ADC, MMAE, and total antibody. Total antibody had the greatest exposure and had a similar PK profile as the ADC. Hence, data on the PK of the ADC and MMAE have been summarized.

Absorption

Maximum concentrations of ADC were typically observed close 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 from 1.2 to 2.7 mg/kg. Steady-state of the ADC was achieved within 21 days with every 3-week dosing of ADCETRIS, consistent with the terminal half-life estimate. Minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule.

The time to maximum concentration for MMAE ranged from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE was achieved within 21 days with every 3 week dosing of ADCETRIS. MMAE exposures decreased with continued administration of ADCETRIS with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses.

Distribution

In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs. In vitro, MMAE was a substrate of P-gp and was not a potent inhibitor of P-gp.

In humans, the mean steady state volume of distribution was approximately 6–10 L for ADC.

Metabolism

In vivo data in animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. 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 CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.

Elimination

MMAE appeared to follow metabolite kinetics, with the elimination of MMAE appearing to be limited by its rate of release from ADC. 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 an ADCETRIS infusion was recovered in both urine and feces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the feces and the majority of the excreted MMAE was unchanged.

Specific Populations

Renal Impairment: [see Use In Specific Populations].

Hepatic Impairment: [see Use in Specific Populations].

Effects of Gender, Age, and Race: Based on the population pharmacokinetic analysis; gender, age, and race do not have a meaningful effect on the pharmacokinetics of brentuximab vedotin.

Clinical Studies

Classical Hodgkin Lymphoma

Clinical Trial In Relapsed Classical HL (Study 1)

The efficacy of ADCETRIS in patients with classical HL who relapsed after autologous hematopoietic stem cell transplantation was evaluated in one open-label, single-arm, multicenter trial. One hundred two patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks. An independent review facility (IRF) performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

The 102 patients ranged in age from 15–77 years (median, 31 years) and most were female (53%) and white (87%). Patients had received a median of 5 prior therapies including autologous hematopoietic stem cell transplantation.

The efficacy results are summarized in Table 4. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 4: Efficacy Results in Patients with Classical Hodgkin Lymphoma (Study 1)

  N=102
Percent (95% CI) Duration of Response, in months
Median (95% CI) Range
CR 32 (23, 42) 20.5 (12.0, NE*) 1.4 to 21.9+
PR 40 (32, 49) 3.5 (2.2, 4.1) 1.3 to 18.7
ORR 73 (65, 83) 6.7 (4.0, 14.8) 1.3 to 21.9+
*Not estimable
+Follow up was ongoing at the time of data submission.

Randomized Placebo-controlled Clinical Trial in Classical HL Post-auto-HSCT Consolidation (Study 3)

The efficacy of ADCETRIS in patients with classical HL at high risk of relapse or disease progression post-auto-HSCT was studied in a randomized, double-blind, placebo-controlled clinical trial. Three hundred twenty-nine patients were randomized 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. Patients in the placebo arm with progressive disease per investigator could receive ADCETRIS as part of a separate trial. The primary endpoint was progression-free survival (PFS) determined by IRF. Standard international guidelines were followed for infection prophylaxis for HSV, VZV, and PCP post-auto-HSCT [see Clinical Trial Experience].

High risk of post-auto-HSCT relapse or progression was defined according to status following frontline therapy: refractory, relapse within 12 months, or relapse ≥ 12 months with extranodal disease. Patients were required to have obtained a CR, PR, or stable disease (SD) to most recent pre-auto-HSCT salvage therapy.

A total of 329 patients were enrolled and randomized (165 ADCETRIS, 164 placebo); 327 patients received study treatment. Patient demographics and baseline characteristics were generally balanced between treatment arms. The 329 patients ranged in age from 18–76 years (median, 32 years) and most were male (53%) and white (94%). Patients had received a median of 2 prior systemic therapies (range, 2–8) excluding autologous hematopoietic stem cell transplantation.

The efficacy results are summarized in Table 5. PFS is calculated from randomization to date of disease progression or death (due to any cause). The median PFS follow-up time from randomization was 22 months (range, 0–49). Study 3 demonstrated a statistically significant improvement in IRF-assessed PFS and increase in median PFS in the ADCETRIS arm compared with the placebo arm. At the time of the PFS analysis, an interim overall survival analysis demonstrated no difference.

Table 5: Efficacy Results in Patients with Classical HL Post-auto-HSCT Consolidation (Study 3)

Progression-free Survival ADCETRIS
N=165
Placebo
N=164
Independent Review Facility
  Number of events (%) 60 (36) 75 (46)
  Median months (95% CI) 42.9+ (30.4, 42.9+) 24.1 (11.5, NE*)
  Stratified Hazard Ratio (95% CI) 0.57 (0.40, 0.81)
  Stratified Log-Rank Test P-value P=0.001
* Not estimable
+ Estimates are unreliable

Figure 1: Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival (Study 3)

Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival - Illustration

Systemic Anaplastic Large Cell Lymphoma

Clinical Trial In Relapsed sALCL (Study 2)

The efficacy of ADCETRIS in patients with relapsed sALCL was evaluated in one open-label, single-arm, multicenter trial. This trial included patients who had sALCL that was relapsed after prior therapy. Fifty-eight patients were treated with 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. An IRF performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

The 58 patients ranged in age from 14–76 years (median, 52 years) and most were male (57%) and white (83%). Patients had received a median of 2 prior therapies; 26% of patients had received prior autologous hematopoietic stem cell transplantation. Fifty percent (50%) of patients were relapsed and 50% of patients were refractory to their most recent prior therapy. Seventy-two percent (72%) were anaplastic lymphoma kinase (ALK)-negative.

The efficacy results are summarized in Table 6. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 6: Efficacy Results in Patients with Systemic Anaplastic Large Cell Lymphoma (Study 2)

  N=58
Percent (95% CI) Duration of Response, in months
Median (95% CI) Range
CR 57 (44, 70) 13.2 (10.8, NE*) 0.7 to 15.9+
PR 29 (18, 41) 2.1 (1.3, 5.7) 0.1 to 15.8+
ORR 86 (77, 95) 12.6 (5.7, NE*) 0.1 to 15.9+
*Not estimable
+ Follow up was ongoing at the time of data submission.

Last reviewed on RxList: 4/1/2016
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.

Related Drugs
Health Resources
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations