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Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial.
- Source :
- Advances in Therapy; Aug2022, Vol. 39 Issue 8, p3635-3653, 19p
- Publication Year :
- 2022
-
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<subscript>meanSS,nominal</subscript>) 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<subscript>meanSS,nominal</subscript>. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0741238X
- Volume :
- 39
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Advances in Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 158139784
- Full Text :
- https://doi.org/10.1007/s12325-022-02170-w