Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Abstract

Purpose: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola.

Methods: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK.

Results: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola.

Conclusions: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.

Keywords: B-cell non-Hodgkin lymphoma; Combination therapy; Drug interactions; Pharmacokinetics; Phase Ib/II; Polatuzumab vedotin.

Fig. 1

Mean (SD) cycle 1 plasma/serum concentration time profiles of pola by study phase and treatment in patients receiving pola 1.0–1.8 mg/kg in combination with R-CHP, or pola 1.4–1.8 mg/kg in combination with G-CHP. Dose-escalation arms are provided in a, c, with dose expansion arms in b, d. Pola analytes include acMMAE (a, b) and unconjugated MMAE (c, d). acMMAE antibody-conjugated MMAE, conc concentration, G-CHP obinutuzumab, cyclophosphamide, doxorubicin, and prednisone, MMAE monomethyl auristatin E, pola polatuzumab vedotin, R-CHP rituximab, cyclophosphamide, doxorubicin, and prednisone, SD standard deviation

Fig. 2

Comparison of dose-normalized exposure of pola by C_max (a, c) or AUC (b, d) within cycle 1 across dose-escalation and expansion arms in patients with B-NHL or DLBCL receiving pola 1.0–1.8 mg/kg + R-CHP or pola 1.4–1.8 mg/kg + G-CHP. Pola analytes include acMMAE (a, b) and unconjugated MMAE (c, d). Vertical boxplots include the median, 10th, 25th, 75th, and 90th percentiles as vertical boxes with error bars for each respective cohort and outliers (black bulleted circles) plotted as single point. acMMAE antibody-conjugated MMAE, AUC_inf area under the concentration–time curve from 0 to infinity, AUC_last area under the concentration–time curve from 0 until the last measurable time point, B-NHL B-cell non-Hodgkin lymphoma, C_max maximum concentration, DLBCL diffuse large B-cell lymphoma, ESC dose-escalation phase, EXP expansion phase, G-CHP obinutuzumab, cyclophosphamide, doxorubicin, and prednisone, MMAE monomethyl auristatin E, pola polatuzumab vedotin, R-CHP rituximab, cyclophosphamide, doxorubicin, and prednisone