imary 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.
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.
MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.
Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. In a 4-week repeat-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis and aspermia were observed. Effects in animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on body weight.
14 CLINICAL STUDIES
14.1 Hodgkin Lymphoma
The efficacy of ADCETRIS in patients with HL who relapsed after autologous stem cell transplant was eva luated 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 3weeks. An independent review facility performed efficacy eva luations 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 stem cell transplant.
The efficacy results are summarized in Table 2. Duration of response is calculated from date of first response to date of progression or data cutoff date.
Table 2: Efficacy Results in Patients withHodgkin Lymphoma *
Not estimable
†
Follow up was ongoing at the time of data submission.
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.
N = 102
Percent ( |
