Complete Bruton Tyrosine Kinase Occupancy Research Articles

BGB-3111, a Highly Specific BTK Inhibitor, Is Well Tolerated and Highly Active in Chinese Patients with Relapsed/Refractory B-Cell Malignancies: Initial Report of a Phase 1 Trial in China

Introduction: BGB-3111 is a potent, specific and irreversible inhibitor of Bruton's tyrosine kinase (BTK). In its first-in-human study in Australia, New Zealand, South Korea, US and Europe, it was demonstrated that BGB-3111 can achieve complete, continuous BTK occupancy in peripheral blood mononuclear cells and lymph nodes, associated with durable clinical responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and Waldenström's macroglobulinemia (WM). Here we report the initial findings of a Phase 1 trial of BGB-3111 in Chinese pts with B-cell malignancies.Patients/ Methods: Chinese pts with relapsed/ refractory B-cell malignancies were enrolled to 1 of 2 dose cohorts of BGB-3111 (320 mg PO QD or 160 mg PO BID). Adverse events (AEs) are reported per CTCAE v4.03, responses per standard criteria according to histology (NHL IWG criteria 2014, CLL IWG criteria 2013, WM IWWM criteria 2013), BTK occupancy determined using an irreversible binding assay in PBMCs.Results: As of 8 June 2017, 21 pts have been enrolled. Median number of prior therapies was 3 (range 1-9). 11 pts received 160 mg PO BID and 10 pts received 320 mg PO QD. The median follow-up time is 8.8 months (range 1.7-11.1 months). All pts were included for safety evaluation and efficacy analyses. Complete BTK occupancy at dosing trough in PBMCs was demonstrated at both dose levels. As of the cut-off date, there was no dose limiting toxicity (DLT). The most frequent grade 3 or above AEs (≥ 10%) were neutropenia (28.6%), thrombocytopenia (14%), leukocytosis (14%), and lymphocytosis (14%). 4 SAEs have been reported, including one event each of toxic epidermal necrolysis (G4), febrile neutropenia (G3), neutropenia (G4), and thrombocytopenia (G4). One MZL pt was discontinued due to G4 toxic epidermal necrolysis and two pts (1 CLL and 1 FL) were discontinued due to disease progression after 169 days (CLL) and 92 days (FL) of treatment. One death (one FL pt) was reported after drug discontinuation due to disease progression. There were no major bleeding and atrial fibrillation reported. Response to treatment by histology is summarized in Table 1 and Figure 1. As of the cut-off date, 18/21 pts remain on study treatment.Conclusions: BGB-3111 is well tolerated and highly active in Chinese pts with B-cell malignancies. The BTK inhibition and anti-tumor activity and safety profile of BGB-311 in Chinese patients are similar to those profiles we have seen in the previously reported data for BGB-3111. Several Phase 2 studies in different indications, including CLL/SLL, MCL, WM, and non-GCB DLBCL, have been initiated in China to further evaluate the efficacy and safety of BGB-3111 in Chinese pts. [Display omitted] DisclosuresXue:BeiGene: Employment. Yang:BeiGene: Employment. Zhang:BeiGene: Employment. Wang:BeiGene: Employment. Huang:BeiGene: Employment. Feng:BeiGene: Employment.

Interest of Dosing of Ibrutinib in B-Cell Lymphoid Malignancies: Data from a Real-Life, Phase 4 Study

Introduction: Therapeutic drug monitoring (TDM) entails the measurement of drug concentrations and the individualization of drug dosages or schedules to maximize therapeutic effects and minimize toxicity. Ibrutinib (IBR), the first-in-class inhibitor of BTK (Bruton tyrosine kinase) is approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL), mantle cell lymphoma (MCL) and Waldenström's disease (WM), at the dose of 420-560mg/d.Drug-drug interactions (DDI), older age, liver diseases have been reported to impact PK parameters of ibrutinib, but dosing is not yet part of clinical practice, despite TDM of imatinib and other kinase inhibitors is routinely used in chronic myeloid leukemia.In this study, we sought to determine whether TDM of ibrutinib should be proposed for patients, in a preliminary cohort of 73 patients included in the PK-e3i trial (NCT02824159).Methods: Serial plasma PK samples were collected at steady-state after one month of therapy in 73 patients: before intake (residual concentration), and then at time 0.5-1-2-4-6h. Key PK parameters for ibrutinib and its metabolite DHD-ibrutinib were calculated: Cmax, Cmin, tmax,AUC24h. Analysis of DDI was made by an oncology pharmacist in 49/73 patients. Treatment-related adverse events were monitored by phonecalls given by an oncology nurse (AMA procedure) and during consultations with hematologist (at least twice a month the first 6 months, then monthly until 12 months, then every 3 months), and severity graded according CTCAE version 4 scale. Efficacy of therapy in CLL patients was assessed with an “effect marker” to demonstrate biological efficacy, the redistribution hyperlymphocytosis seen in 70% of patients the first month of therapy.Results: we reported very similar PK results for ibrutinib as compared to pivotal phase 1 trials in CLL and other B-cell lymphoid malignancies (Advani RH, J Clin Oncol 2013, Byrd JC, New Engl J Med 2013). Mean peak plasma concentrations were observed 1-2h after dosing, Cmax and AUC results showing an important inter-patient heterogeneity. Median Cmax was 150ng/ml (8.2-596ng/ml), and median AUC24h was 412.4 ng h/mL ((32.2-2906 ng h/mL). According to published phase I trials, complete or near complete BTK occupancy was observed in patients with AUCs exceeding 160 ng h/mL, suggesting ibrutinib dose might have been supramaximal in 67 of our patients. Adverse events the first 3 months were seen in 96% (grade 1), 63% (grade 2), 25% (grade 3) and 6.5% (grade 4), respectively. We plotted AUC results for the total cohort of 73 patients (Figure 1), and for 49 patients with adverse events monitoring available at 3 months (9/49 needed drug dose reduction due to toxicity) (Figure 2), both emphasizing the absence of correlations between AUC levels and toxicities. We next splited up toxicities into 10 sub-groups (bleeding, cardiac, liver, muscle, joint, skin, infection, gastro-intestinal, hematologic, neurologic disorders). Again, we could not identify a specific organ toxicity associated with a significant increase of Cmax or AUC24h, nor we could identify a specific DDI signature explaining side effects in our patents (data not shown: 13/49 had CYP3A4 inhibitors, 25/49 had pgp inhibitors).In 45 CLL patients with PK parameters and lymphocyte counts available after one month of therapy, we made the intriguing observation that lower Cmax correlated with the lack of observable, transient hyperlymphocytosis (a class-effect of ibrutinib, correlating with PFS in the Resonate trial) (Figure 3). Altogether, our data did not find any positive correlation between high ibrutinib exposure and efficacy or safety profile.Conclusions: our preliminary results suggested that higher Cmax and AUC24h did not correlate neither to efficacy nor to classical toxicities reported with ibrutinib intake. On one hand, we think that dosing intra-cellular concentrations could be more reliable than in plasma. On the other hand, we could consider TDM of ibrutinib in the context of a clinical trial reducing the doses of drug over time, to limit clinical and financial toxicity of this highly efficient drug. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Twice Daily Dosing with the Highly Specific BTK Inhibitor, Bgb-3111, Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and Is Associated with Durable Responses in Patients (pts) with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Twice Daily Dosing with the Highly Specific BTK Inhibitor, Bgb-3111, Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and Is Associated with Durable Responses in Patients (pts) with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)