Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432
Authors: Venkatakrishnan Karthik , Ramanathan Ramesh K , Sarantopoulos John , Mulkerin Daniel L , Shibata Stephen I , Hamilton Anne , Dowlati Afshin , Mani Sridhar , Rudek Michelle A , Ivy Percy , Takimoto Chris H , Neuwirth Rachel , Parasuraman Sudha , LoRusso Patricia M 
Published: October 2019

Abstract
Abstract 3975
Background: Bortezomib (btz, VELCADE®) is approved in the US for the treatment of patients (pts) with multiple myeloma, and for the treatment of pts with mantle cell lymphoma who have received at least one prior therapy. Btz is oxidatively metabolized by hepatic cytochrome P450 enzymes to pharmacologically inactive deboronated metabolites. Thus, btz pharmacokinetics (PK) may be altered in pts with hepatic impairment (HI). This phase 1 study was undertaken to evaluate the PK and safety of btz in pts with varying grades of HI and to inform dosing recommendations in these subpopulations. Here we present the available interim results. Methods: Pts with advanced malignancies were assigned to four groups based on hepatic function (bilirubin and aspartate aminotransferase [AST] levels relative to the upper limit of normal [ULN]) using the classification developed for organ dysfunction studies by the National Cancer Institute's Cancer Therapy Evaluation Program. Normal function was defined as bilirubin and AST ≤ULN. Pts with mild HI had bilirubin ≤ULN and AST >ULN, or bilirubin >1.0–1.5 × ULN (with any AST). Moderate and severe HI were defined as bilirubin >1.5–3 × ULN and >3 × ULN, respectively, with any AST. Pts received btz on days 1, 4, 8, and 11 of 21-day cycles. Pts with normal hepatic function received btz at the standard dose of 1.3 mg/m2. Pts with severe, moderate, and mild HI received escalating doses of btz from starting doses of 0.5, 0.7, and 1.0 mg/m2, respectively, via a standard 3+3 design to 1.3 mg/m2. Serial blood samples were collected for 24 hours post-dose on days 1 and 8 of cycle 1 for measurement of btz plasma concentrations. Individual values of dose-normalized (DN) area under the concentration–time curve from time zero to the point of last quantifiable concentration (AUC) and maximum concentration (Cmax) were calculated by noncompartmental analysis. PK parameters were summarized by hepatic function and subject to an analysis of variance to estimate the ratio of geometric means and 90% confidence intervals (CIs) for each HI group relative to the control group. Results: A total of 53 pts were treated, 14 with normal hepatic function, and 16, 9, and 14 with mild, moderate, and severe HI, respectively. Median age was 62 years (range 30–85), 53% were female, 94% were white, and 11/58/30% had ECOG performance status 0/1/2. Dose escalation proceeded to 1.3 mg/m2 in pts with mild HI; data collection is ongoing at 1.0 mg/m2 in pts with moderate and severe HI. The most common adverse events (AEs) were fatigue (53%), nausea (42%), and dyspnea (32%). For most AEs, no association was apparent between increased incidence and poorer hepatic function; the incidence of elevated AST was 7, 25, 33, and 36% in the normal group and mild, moderate, and severe HI groups, respectively. PK data were available for 51 pts. Geometric mean DN AUC was 30.2, 23.0, 50.3, and 47.7 (ng.hr/mL)/(mg/m2) on day 1 and 52.2, 51.9, 83.4, and 80.3 (ng.hr/mL)/(mg/m2) on day 8 in pts with normal hepatic function and mild, moderate, and severe HI, respectively. Respective values for geometric mean DN Cmax were 56.7, 38.2, 66.0, and 84.2 (ng/mL)/(mg/m2) on day 1, and 88.9, 79.6, 59.2, and 96.1 (ng/mL)/(mg/m2) on day 8. Geometric least square mean ratios for DN AUC and DN Cmax between groups are shown in the table. Compared to pts with normal hepatic function, mild HI did not alter DN AUC and DN Cmax. However, mean DN AUC was increased by approximately 60% in pts with moderate or severe HI. Conclusions: Pts with mild HI do not require a starting dose adjustment and should be treated per the recommended dose of btz. Pts with moderate or severe HI should be started at a reduced dose of 0.7 mg/m2 during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on pt tolerance. These data have resulted in an update to the US Prescribing Information for VELCADE®.
Comparison vs normal Geometric least square mean ratio (90% CI) Day 1 Day 8 DN AUC Mild HI 0.833 (0.603–1.151) 0.954 (0.664–1.371) Moderate HI 1.662 (1.136–2.430) 1.538 (0.969–2.440) Severe HI 1.578 (1.139–2.186) 1.477 (1.046–2.085) Average of moderate/severe HI 1.619 (1.199–2.186) 1.507 (1.075–2.113) DN Cmax Mild HI 0.697 (0.446–1.090) 0.879 (0.528–1.463) Moderate HI 1.162 (0.688–1.962) 0.612 (0.318–1.178) Severe HI 1.483 (0.947–2.323) 1.023 (0.633–1.653) Average of moderate/severe HI 1.313 (0.868–1.986) 0.791 (0.493–1.271)

Disclosures:
Venkatakrishnan: Millennium Pharmaceuticals: Employment. Off Label Use: Discussion of Velcade in patients with advanced non-hematologic malignancies is included. Takimoto:Johnson & Johnson: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. LoRusso:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.