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 (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; 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.

• Authors: Divya Samineni, Leonid Gibiansky, Bei Wang, Shweta Vadhavkar, Richa Rajwanshi, Maneesh Tandon, Arijit Sinha, Othman Al-Sawaf, Kirsten Fischer, Michael Hallek, Ahmed Hamed Salem, Chunze Li, Dale Miles
• Journal: Advances in therapy (Adv Ther) Vol. 39 Issue 8 Pg. 3635-3653 (08 2022) ISSN: 1865-8652 [Electronic] United States
• PMID: 35708885 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Bridged Bicyclo Compounds, Heterocyclic
• Sulfonamides
• venetoclax
• obinutuzumab

Topics

• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics)
• Bayes Theorem
• Bridged Bicyclo Compounds, Heterocyclic
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Sulfonamides