Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity

Abstract

Background: Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.

Methods: In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.

Findings: 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218).

Interpretation: Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.

Funding: Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Figure 1. Navitoclax Dosing Schedule

(a). Intermittent (14/21) dosing schedule. For Cycle 1, navitoclax was administered on day –3 to assess pharmacokinetics (PK) and food effect. Beginning on Cycle 1 day 1, patients were dosed non-fasting for 14 consecutive days on days 1–14 of a 21- day dosing cycle. In subsequent cycles, patients receive drug on D1–14 followed by 7 days off. (b). Continuous (21/21) dosing schedule. On cycle 1, patients received a 150 mg lead-in dose for 7–14 days followed by continuous dosing at their assigned dose level.

Figure 2. Pharmacokinetic Profile of Navitoclax

Line graph of mean (±SD) navitoclax plasma concentrations vs. time profiles in patients at Days -3 (fasting), 1 (non-fasting) and 14 (non-fasting) following oral administration of navitoclax at 10–440 mg dose levels on the 14/21-day dosing schedule.

Figure 3. Pharmacodynamic Effects of Navitoclax

(a) Bar graph of median absolute circulating CD3 cells/µl at baseline (n=20 patients), day 14 of cycle 1 (n=19 patients) and the final visit (n=16 patients) at the end of navitoclax treatment, and the median change on day 14 of cycle 1 and final visit. Patients received at least 200 mg navitoclax for at least two cycles on either the 14/21 or 21/21day schedule. The mean (range) time between baseline and final visit was 89 (29–332) days and the mean (range) daily drug exposure was 255 (137–388) mg of navitoclax. P-value was calculated using a Sign-test because the data were skewed. (b) Line graph of platelet nadirs over time at 315 mg on the 14/21-day schedule (n=9 patients) (left panel) and at 275 mg on the 21/21-day schedule (n=6 patients) (right panel). (c) Platelet nadir versus navitoclax area under the curve at multiple dose levels (n=35 patients). R-value was calculated by using SigmaPlot 9.0.

Figure 4. Antitumor Activity of Navitoclax

Waterfall plot of maximal percent change in tumor size from baseline using standard criteria.(12, 13) Tumor subtypes are shown on the x-axis: DLBCL-diffuse large B-cell lymphoma; FL-follicular lymphoma; MCL-mantle cell lymphoma; CLL/SLL-chronic lymphocytic leukemia/small lymphocytic lymphoma; MZL-marginal zone lymphoma; HL-classical Hodgkin’s lymphoma; and NK/T-natural killer-T-cell lymphoma.