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Population Pharmacokinetics and Exposure–Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma.
- Source :
- Advances in Therapy; Jan2022, Vol. 39 Issue 1, p598-618, 21p
- Publication Year :
- 2022
-
Abstract
- Introduction: Outcomes remain poor in patients with diffuse large B cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure–response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase 1b/2 CAVALLI study, to confirm dose selection for future studies. Methods: Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400–800 mg venetoclax (cycle 1: days 4–10; cycles 2–8: days 1–10) in combination with R for eight cycles and CHOP for 6–8 cycles. A legacy PopPK model for venetoclax was used to describe the observed data and provide post hoc PK parameters. Venetoclax steady-state exposure (AUC<subscript>ss</subscript>) was used to predict clinical efficacy, safety, or tolerability. To isolate the effect of venetoclax, ER analyses referenced data from the R-CHOP arm of a historical control study, GOYA, in 1L DLBCL. Results: There was no significant association between venetoclax AUC<subscript>ss</subscript> and progression-free survival or complete response either for all-comers or the BCL-2-immunohistochemistry-positive subpopulation. No statistically significant trends were observed with venetoclax AUC<subscript>ss</subscript> and the key grade ≥ 3 adverse events and serious adverse events. Similar dose intensities were observed for venetoclax and R-CHOP components across venetoclax exposures, suggesting venetoclax did not impact delivery of the R-CHOP backbone. Conclusions: The PopPK and ER analyses, in addition to the positive benefit–risk observed in the clinical data, support the selection of 800 mg venetoclax given with R-CHOP for future studies in BCL-2-immunohistochemistry-positive patients with 1L DLBCL. Trial Registration: ClinicalTrials.gov Identifier NCT02055820. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0741238X
- Volume :
- 39
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Advances in Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 154979642
- Full Text :
- https://doi.org/10.1007/s12325-021-01919-z