Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial.

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.

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.

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 (AUCss) 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 AUCss 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 AUCss 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.

Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant.

The limited effectiveness of rituximab plus intravenous immunoglobulin (IVIG) in desensitization may be due to incomplete B cell depletion. Obinutuzumab is a type 2 anti-CD20 antibody that induces increased B cell depletion relative to rituximab and may therefore be more effective for desensitization. This open-label phase 1b study assessed the safety, pharmacokinetics, and pharmacodynamics of obinutuzumab in highly sensitized patients with end-stage renal disease. Patients received 1 (day 1, n = 5) or 2 (days 1 and 15; n = 20) infusions of 1000-mg obinutuzumab followed by 2 doses of IVIG on days 22 and 43. Eleven patients received additional obinutuzumab doses at the time of transplant and/or at week 24. The median follow-up duration was 9.4 months. Obinutuzumab was well tolerated, and most adverse events were grade 1-2 in severity. There were 11 serious adverse events (SAEs) in 9 patients (36%); 10 of these SAEs were infections and 4 occurred after kidney transplant. Obinutuzumab plus IVIG resulted in profound peripheral B cell depletion and appeared to reduce B cells in retroperitoneal lymph nodes. Reductions in anti-HLA antibodies, number of unacceptable antigens, and the calculated panel reactive antibody score as centrally assessed using single-antigen bead assay were limited and not clinically meaningful for most patients (NCT02586051).

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data.

OBJECTIVES: Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited. METHODS: We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501). RESULTS: After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed. Retrospectively reported pregnancies (n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group. No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome. CONCLUSIONS: No indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.