Population Pharmacokinetics (PPK) and Exposure-Response to Support Body Surface Area (BSA)-Based Dosing of Brentuximab Vedotin in Pediatric Patients with Advanced-Stage Newly-Diagnosed Hodgkin Lymphoma (HL)

Abstract

Introduction Brentuximab vedotin is an antibody-drug conjugate (ADC), consisting of antibody cAC10 specific to human CD30 and the antimicrotubule agent monomethyl auristatin E (MMAE), conjugated by a protease-cleavable linker. PPK models were developed to identify factors impacting the pharmacokinetics of ADC and MMAE, and exposure-response analyses were performed to assess the risk-benefit profiles of brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A+AVD) to support BSA-based dosing of brentuximab vedotin in pediatric patients with advanced-stage newly-diagnosed HL. Methods Data from two open-label phase 1/2 pediatric studies were included in the PPK analysis: study C25002 (NCT01492088), which was a dose-escalation study (brentuximab vedotin 1.4-1.8 mg/kg every 3 weeks) in patients with relapsed or refractory systemic anaplastic large cell lymphoma or HL, and study C25004 (NCT02979522) in patients with advanced-stage, newly-diagnosed HL (brentuximab vedotin 48 mg/m2 every 2 weeks [Q2W] +AVD; A 25 mg/m2, V 6 mg/m2, D 375 mg/m2). Samples for measuring ADC and MMAE concentrations and immunogenicity assessment were collected. Sources of brentuximab vedotin pharmacokinetic variability were quantified using nonlinear mixed-effects modeling. ADC exposures achieved by BSA-based dosing of brentuximab vedotin in pediatric patients were compared to those in adults who received weight-based dosing of brentuximab vedotin in the ECHELON-1 trial (NCT01712490). Exposure-response analyses included patients in study C25004 treated with brentuximab vedotin 48 mg/m2 Q2W in combination with AVD. Relationships between ADC/MMAE exposures, progression-free survival (PFS), and incidence of adverse events (AEs) were analyzed by logistic regression in patients receiving A+AVD. Results Data from 95 patients (6-17 years) informed pharmacokinetics models of ADC (linear 3-compartment with zero-order input and first-order elimination) and MMAE (2-compartment with first-order elimination and formation of MMAE from ADC). BSA (0.79-2.03 m2) and albumin level (23-51 g/L) were significant covariates for clearance of ADC and MMAE. Age, body weight, sex, and race were not identified as covariates for ADC and MMAE pharmacokinetics. Albumin concentrations did not result in clinically meaningful change in clearance of ADC and MMAE. BSA-based brentuximab vedotin dosing resulted in similar systemic exposures of ADC and MMAE across age groups (<12 [n=23], 12-16 [n=56], and >16 years [n=16]). In exposure-response analyses (n=59), steady-state ADC exposures (area under the curve [AUC]) with BSA-based dosing of brentuximab vedotin at 48 mg/m2 Q2W in pediatric patients were comparable to those with weight-based dosing of brentuximab vedotin at 1.2 mg/kg Q2W in adults in the ECHELON-1 trial (Figure). A significant increase (p<0.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE, consistent with what has been observed in adult patients. No apparent relationship was identified between ADC exposure and the incidence of peripheral neuropathy, grade ≥3 neutropenia, febrile neutropenia, or grade ≥3 treatment-emergent AEs, or between ADC/MMAE exposure and PFS. Conclusions PPK and exposure-response analyses support brentuximab vedotin 48 mg/m2 Q2W in combination with AVD as a treatment option for pediatric patients with advanced-stage newly-diagnosed HL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal