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Pharmacokinetics and exposure–response analysis of venetoclax+obinutuzumab in chronic lymphocytic leukaemia: phase 1b study and phase 3 CLL14 trial
  • +10
  • 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
Divya Samineni
Genentech, Inc.

Corresponding Author:[email protected]

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Leonid Gibiansky
QuantPharm LLC
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Bei Wang
Genentech, Inc.
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Shweta Vadhavkar
Genentech, Inc.
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Richa Rajwanshi
VRAY Pharma Consulting
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Maneesh Tandon
Roche Products Ltd
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Arijit Sinha
Roche Products Ltd
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Othman Al-Sawaf
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital
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Kirsten Fischer
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital
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Michael Hallek
Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital
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Ahmed Hamed Salem
AbbVie Inc.
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Chunze Li
Genentech, Inc.
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Dale Miles
Genentech, Inc.
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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.