Universität zu Köln

Samineni, Divya, Gibiansky, Leonid, Wang, Bei, Vadhavkar, Shweta, Rajwanshi, Richa, Tandon, Maneesh, Sinha, Arijit, Al-Sawaf, Othman, Fischer, Kirsten, Hallek, Michael ORCID: 0000-0002-7425-4455, Salem, Ahmed Hamed, Li, Chunze and Miles, Dale (2022). Pharmacokinetics and Exposure-Response Analysis of Venetoclax plus Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Adv. Ther., 39 (8). S. 3635 - 3654. NEW YORK: SPRINGER. ISSN 1865-8652

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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,C-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,C-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Samineni, Divya UNSPECIFIED UNSPECIFIED UNSPECIFIED Gibiansky, Leonid UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Bei UNSPECIFIED UNSPECIFIED UNSPECIFIED Vadhavkar, Shweta UNSPECIFIED UNSPECIFIED UNSPECIFIED Rajwanshi, Richa UNSPECIFIED UNSPECIFIED UNSPECIFIED Tandon, Maneesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinha, Arijit UNSPECIFIED UNSPECIFIED UNSPECIFIED Al-Sawaf, Othman UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED orcid.org/0000-0002-7425-4455 UNSPECIFIED Salem, Ahmed Hamed UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Chunze UNSPECIFIED UNSPECIFIED UNSPECIFIED Miles, Dale UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687377
DOI:	10.1007/s12325-022-02170-w
Journal or Publication Title:	Adv. Ther.
Volume:	39
Number:	8
Page Range:	S. 3635 - 3654
Date:	2022
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1865-8652
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BCL-2 INHIBITOR; 17P DELETION; OPEN-LABEL; CHLORAMBUCIL; MULTICENTER; RITUXIMAB; EFFICACY Multiple languages Medicine, Research & Experimental; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68737