Pharmacokinetics and exposure–response analysis of
venetoclax+obinutuzumab in chronic lymphocytic leukaemia: phase 1b study
and phase 3 CLL14 trial
Abstract
Aims: To investigate pharmacokinetics (PK) and exposure-response of the
400 mg once daily venetoclax dose regimen in combination with
obinutuzumab in the phase 3 CLL14 study approved for the treatment of
first-line (1L) chronic lymphocytic leukaemia (CLL). Methods: Parameter
estimates and uncertainty estimated by a previously developed population
PK (popPK) model were used as informative priors for this analysis. They
were re-estimated, 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 CLL14 data, with steady-state exposure
at the nominal target dose (CmeanSS,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 CmeanSS,nominal. Results: PK data from 274
patients (CLL14, n=194; phase 1b dose-finding study GP28331, n=80) were
included. The final model provided good fit of 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, -safety and
-tolerability analyses support the 400 mg once-daily venetoclax dose
plus obinutuzumab in patients with 1L CLL.