Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial

Abstract

Introduction: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.

Methods: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (C_{meanSS,nominal}) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥ 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C_{meanSS,nominal}.

Results: PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles.

Conclusion: PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL.

Clinical trial registration: ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.

Keywords: Cancer; Drug safety; Effectiveness; Pharmacokinetics.

Fig. 1

Prediction-corrected VPC using the final popPK model to predict the observed data for CLL14 (a) and GP28331 (b). CI confidence interval, h hours, popPK population pharmacokinetics, VPC visual predictive check. Points are prediction-corrected venetoclax concentrations plotted vs. time after most recent venetoclax dose. The lines show median (red), and the 5th and 95th percentiles (blue) of the prediction-corrected venetoclax concentrations. The shaded regions show the 90% CIs on these quantities obtained by simulations. The simulated values were computed from 500 trials with dosing, sampling, and the covariate values of the analysis dataset

Fig. 2

Kaplan-Meier analysis of time to progression (investigator data). Exposure groups correspond to quartiles of C_{meanSS,nominal}. C_{meanSS,nominal} nominal exposure at steady state, PFS progression-free survival

Fig. 3

Logistic regression analyses of exposure-safety relationships for treatment-emergent grade ≥ 3 neutropenia (a), grade ≥ 3 thrombocytopenia (b), grade ≥ 3 infections (c), and SAEs (d). CI confidence interval, glm generalized linear models, QD once-daily, SAE serious adverse event. The red solid line and blue shaded area represent the logistic regression model prediction and 90% CI of predictions, respectively. Points show exposure of individual patients with events (p = 1) and without events (p = 0). Black squares and vertical black lines show observed fraction of patients with events in each exposure group and 90% CI for these fractions. Dashed vertical lines show bounds of exposure groups. Blue line and point indicate point estimate and 95% coverage interval of steady-state exposure following 400 mg QD doses, respectively. p value is provided by glm() function

Fig. 4

Venetoclax (a) and obinutuzumab (b) dose intensity vs. venetoclax exposure. C_{meanSS,nominal} nominal exposure at steady state. Circles correspond to individual dose intensity values. C_{meanSS,nominal} was used as a measure of exposure. The bold red lines are the LOWESS (local weighted scatterplot smoothing) trend lines. Median values are designated by black lines in the center of the blue boxes. Boxes indicate the interquartile range (IQR). Whiskers represent 1.5 × IQR