ALBERT

Description: Introduction: Venetoclax, a selective BCL2 inhibitor, is approved for treatment of chronic lymphocytic leukemia in patients who received at least one prior therapy and is being studied in several other hematological malignancies including acute myeloid leukemia (AML). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax in patients with newly diagnosed AML who are not eligible for standard anthracycline-based induction therapy treated with venetoclax plus a hypomethylating agent (HMA) either azacitidine or decitabine, or low dose cytarabine (LDAC) to inform dose selection. Methods: A population pharmacokinetic model for venetoclax was developed using data from 336 AML subjects. Post hoc pharmacokinetic parameters generated from the model were used to calculate the exposure metric, steady-state area under the plasma concentration-time curve (AUCss), in the exposure-efficacy and exposure-safety analyses. Multivariate cumulative logistic regression analyses were performed using efficacy and safety data. In total, for the venetoclax plus HMA combination, 201 subjects were included in the exposure-efficacy and 212 subjects were included in the exposure-safety analyses. For the venetoclax plus LDAC combination, 83 subjects were included in the exposure-efficacy and 92 subjects were included in the exposure-safety analyses. Predictions based on the exposure-response model parameter estimates were used to explore the exposure- and dose-response relationships and select the optimal venetoclax dose. Results: Venetoclax in Combination with HMAs: Simulations indicated that venetoclax dosage of 400 mg once daily (QD) in combination with HMAs maximizes the probability of a typical subject achieving a response of complete remission (CR).. Venetoclax exposure-response relationship was similar for both azacitidine and decitabine combination (P 〉 0.05). For exposure-safety analyses, only treatment-emergent Grade ≥ 3 infections showed a statistically significant relationship with venetoclax exposures in combination with HMAs across the tested venetoclax dose range (400 - 1200 mg QD). The probability of occurrence of treatment-emergent Grade ≥ 3 infections at venetoclax dose of 400 mg and 800 mg was 51% (95% CI: [43, 58%]) and 59% (95% CI: [50, 66%]), respectively. Venetoclax in Combination with LDAC: A statistically significant association of best responses was determined with increasing steady-state area under the plasma concentration-time curve (AUCss). Based on the tolerability data, the probability of achieving CR with incomplete count recovery (CRi) or better, and CR was predicted for doses up to 600 mg. The predicted probability of achieving CRi or better was approximately 46% (95% CI: [37, 55%]) and 55% (95% CI: [45 - 66%]) at exposures associated with the 400 mg and 600 mg dosage regimen given once daily, respectively. Conclusions: The venetoclax exposure- efficacy and exposure-safety analyses supported the 400 mg QD dosage regimen of venetoclax in combination with the HMAs and 600 mg QD dosage regimen of venetoclax in combination with LDAC in treatment naïve AML patients who are ineligible for standard induction chemotherapy. Disclosures Agarwal: AbbVie: Employment, Equity Ownership. Gopalakrishnan:AbbVie: Employment, Equity Ownership. Mensing:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Friedel:AbbVie: Employment, Equity Ownership. Menon:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership.

Description: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Description: Introduction: Venetoclax (VEN), an orally bioavailable selective BCL-2 inhibitor, was granted accelerated approval by the FDA for the treatment of acute myeloid leukemia (AML) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships using data from the nonrandomized Phase 1/2 studies and the confirmatory Phase 3 studies in subjects with treatment-naïve AML who are ineligible for intensive chemotherapy. Methods: A population pharmacokinetic (PK) model for VEN was characterized using data from 771 AML subjects across 5 Phase 1 - 3 studies including subjects with relapsed/refractory AML and subjects with treatment-naïve AML who were ineligible for intensive chemotherapy. PK parameters from this model were used to calculate the exposure metric, the area under the plasma concentration-time curve at steady-state (AUCss), for exposure-efficacy and exposure-safety analyses. Logistic regression and Cox proportional-hazards models were used to characterize the exposure-response relationships for overall survival, event-free survival, and conversion to post-baseline transfusion independence for red blood cells or platelets as well as key safety endpoints of treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, and infections. Additionally, best overall response of complete remission (CR), CR + CR with incomplete blood count recovery (CRi), and CR + CR with partial hematological recovery (CRh) were also characterized in the exposure-response analyses. Separate analyses were performed for VEN + HMA and VEN + LDAC, including subjects taking placebo (PBO) + HMA or PBO + LDAC, respectively, to inform the intercepts. A total of 575 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + HMA and 279 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + LDAC. Results: VEN + HMA: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + HMA as compared to PBO in combination with azacitidine (AZA). When PBO patients were included, significant exposure-response relationships between VEN exposure and overall survival and event-free survival were identified, and a maximal effect (Emax) model best described the statistically significant positive relationships between VEN exposure and best overall response of CR + CRi and CR + CRh. However, there were no apparent relationships between VEN exposure and any efficacy endpoint without the inclusion of PBO subjects, suggesting that the beneficial effect of VEN is already maximized in the dose range studied (400 to 1200 mg daily [QD]). No exposure-response relationship was identified between VEN exposure and treatment-emergent Grade ≥ 3 thrombocytopenia or infections. An Emax model best described the statistically significant relationship between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, consistent with the clinical finding that subjects in the VEN + HMA treatment arms had higher rates of reported neutropenia than those in the PBO + AZA arm. VEN + LDAC: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + LDAC as compared to PBO + LDAC. With PBO subjects included, an Emax model best described the statistically significant relationships between VEN exposure and best overall response of CR, CR + CRi, and CR + CRh, with probability of response plateauing at exposures corresponding to 600 mg QD of VEN. There were no apparent relationships between VEN exposure and any efficacy endpoint when the PBO subjects were excluded from analysis, indicating that the beneficial effect of VEN is already maximized at 600 mg QD. Although reported rates of treatment-emergent Grade ≥ 3 neutropenia were higher in the VEN + LDAC treatment arms as compared to PBO + LDAC, no significant exposure-response relationships were found between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, or infections. Conclusion: The VEN exposure-efficacy and exposure-safety analyses confirm the benefit of adding VEN to either HMA or LDAC and support the dose regimens of VEN 400 mg QD in combination with an HMA and VEN 600 mg QD in combination with LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy. Disclosures Eckert: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Smith:Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy. Wei:AbbVie Inc.: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding. Hayslip:Abbvie Inc: Current Employment, Other: may hold stock or other options. Miles:Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Mensing:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Zha:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Description: M. Badawi and S. Gopalakrishnan equally contributed to this work Introduction: Venetoclax is a selective BCL2 inhibitor approved for patients with CLL and patients with newly diagnosed AML who are ineligible for induction chemotherapy. Venetoclax is currently being evaluated in other hematologic and solid tumors in both adult and pediatric populations. In this analysis, we characterized the pharmacokinetics and exposure response relationships of venetoclax to guide dose selection of venetoclax in combination with high dose cytarabine (HDAC) in pediatric patients with relapsed or refractory AML. Methods: A population PK model describing venetoclax PK in pediatric patients was developed using data from 121 subjects across three venetoclax studies that tested venetoclax at 400-800 mg doses across different tumors. The model accounted for the CYP3A4 developmental changes in early years of life using a maturation function and allometric scaling was also incorporated in the model to account for growth and body size effect. Individual subject average venetoclax plasma concentration (Cavg) up to the event of interest, determined based on the population PK analysis using the post-hoc empirical Bayesian parameter estimates, was used as an exposure metric to explore exposure-efficacy and exposure-safety relationships. Data from subjects with AML (database version 23-Mar-2020) who received venetoclax in combination with either azacitidine, decitabine, or cytarabine were included in the exposure-efficacy and exposure-safety analyses. The population PK model was then used to simulate venetoclax exposures in pediatric subgroups to guide dose selection for future trials. Results: Population PK estimates (clearance, volume of distribution, rate of absorption and peripheral volume of distribution) were comparable to previously reported estimates. Additionally, weight was identified as a statistically significant covariate on clearance and volume of distribution. Exposure-response analyses showed a flat relationship between venetoclax exposures and efficacy in patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine. Moreover, venetoclax exposures did not correlate with incidence of neutropenia. Specifically, in AML patients who received venetoclax in combination with HDAC (〉500-2000 mg/m2/day, n=15), higher venetoclax exposures were not associated with better clinical response. A 600 mg dose of venetoclax was selected based on high response rates observed in the clinic. Venetoclax doses for pediatric subgroups were selected based on weight (allometric scaling) for children aged ≥ 2 years old and based on weight and CYP3A ontogeny for children aged 〈 2 years old. Table 1 presents the selected doses for the pediatric age and weight groups. Simulations of exposures (steady state area under the curve [AUCss]) using the population PK model for the pediatric age and weight groups are represented in Figure 1. Reasonable overlap in exposures was observed across the pediatric groups. Conclusions: Exposure-efficacy and exposure-safety showed lack of superiority of higher exposures and hence, 600 mg QD venetoclax in combination with HDAC was selected for pediatric patients with relapsed or refractory AML in future trials. Simulations of exposures demonstrated that the selected age- and weight-based doses would achieve exposures in pediatric subgroups comparable to that expected in adults receiving a 600 mg dose of venetoclax. Disclosures Badawi: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Engelhardt:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Karol:AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Rubnitz:AbbVie Inc.: Research Funding. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options.