Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial
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, 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
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.
Keywords: Cancer; Drug safety; Effectiveness; Pharmacokinetics.
© 2022. The Author(s).
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References
- Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines. Ann Oncol. 2020;32:23–33. doi: 10.1016/j.annonc.2020.09.019.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387.
- Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2017;92:946–965. doi: 10.1002/ajh.24826.
- Freise KJ, Jones AK, Eckert D, et al. Impact of venetoclax exposure on clinical efficacy and safety inpatients with relapsed or refractory chronic lymphocytic leukemia. Clin Pharmacokinet. 2017;56:515–523. doi: 10.1007/s40262-016-0453-9.
- Parikh A, Gopalakrishnan S, Freise KJ, et al. Exposure–response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma. Leuk Lymphoma. 2018;59:871–879. doi: 10.1080/10428194.2017.1361024.
- Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826–833. doi: 10.1200/JCO.2016.70.4320.
- Seymour JF, Kipps TJ, Eichhorst E, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107–1120. doi: 10.1056/NEJMoa1713976.
- Deng R, Gibianksy L, Lu T, et al. Exposure-response analysis of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia: pooled results from a phase 1b study and the phase 3 MURANO study. Leuk Lymph. 2020;61:56–65. doi: 10.1080/10428194.2019.1657575.
- VENCLEXTA™: highlights of prescribing information. VENCLEXTA™ (venetoclax) tablets, for oral use. Initial US Approval: 2016. Revised: June 2018. North Chicago, IL, USA: AbbVie Inc.
- Mössner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type of anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393–4402. doi: 10.1182/blood-2009-06-225979.
- Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2010;152:295–306. doi: 10.1111/j.1365-2141.2010.08428.x.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110. doi: 10.1056/NEJMoa1313984.
- Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphoytic leukemia and comorbidities: final survival analysis of the CLL11 study [EHA 2018 Abstract S151] HemaSphere. 2018;2(S1):30.
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225–2236. doi: 10.1056/NEJMoa1815281.
- Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21:1188–1200. doi: 10.1016/S1470-2045(20)30443-5.
- Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymhocyti leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomised phase 3 CLL14 trial [EHA 2020 Abstract S155] HemaSphere. 2020;4(S1):30.
- Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;133:2765–2775. doi: 10.1182/blood-2019-01-896290.
- Salem AH, Hu B, Freise KJ, et al. Evaluation of the pharmacokinetic interaction between venetoclax, a selective BCL-2 inhibitor, and warfarin in healthy volunteers. Clin Drug Investig. 2017;37:303–309. doi: 10.1007/s40261-016-0485-9.
- Liu H, Michmerhuizen MJ, Lao Y, Wan K, et al. Metabolism and disposition of a novel B-cell lymphoma-2 inhibitor venetoclax in humans and characterisation of its unusual metabolites. Drug Metab Dispos. 2017;45:294–305. doi: 10.1124/dmd.116.071613.
- Jones AK, Freise KJ, Agarwal SK, Humerickhouse RA, Wong SL, Salem AH. Clinical predictors of venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J. 2016;18:1192–1202. doi: 10.1208/s12248-016-9927-9.
- Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2011) Ellicott City: Icon Development Solutions; 2011.
- Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukemia with 17p deletion: a multicenter, open-label phase 2 study. Lancet Oncol. 2016;17:768–778. doi: 10.1016/S1470-2045(16)30019-5.
- Salem AH, Dunbar M, Agarwal SK. Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia. Anticancer Drugs. 2017;28:911–914. doi: 10.1097/CAD.0000000000000522.
- Deng R, Gibianksy L, Lu T, et al. Bayesian population model of the pharmacokinetics of venetoclax in combination with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from the phase III MURANO study. Clin Pharmacokinet. 2019;58:1621–1634. doi: 10.1007/s40262-019-00788-8.
- Agarwal SK, Salem AH, Danilov AV, et al. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol. 2017;83:846–854. doi: 10.1111/bcp.13175.
- Freise KJ, Shebley M, Salem AH. Quantitative prediction of the effect of CYP3A inhibitors and inducers on venetoclax pharmacokinetics using a physiologically based pharmacokinetic model. J Clin Pharmacol. 2017;57:796–804. doi: 10.1002/jcph.858.
- Freise KJ, Hu B, Salem AH. Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics. Eur J Clin Pharmacol. 2018;74:413–421. doi: 10.1007/s00228-017-2403-3.
- Agarwal SK, DiNardo CD, Potluri J, et al. Management of venetoclax-posaconazole interaction in acuter myeloid leukemia patients: evaluation of dose adjustments. Clin Ther. 2017;39:359–367. doi: 10.1016/j.clinthera.2017.01.003.
Source: PubMed