Ongoing phase I studies of ABT-263: Mitigating Bcl-XL induced thrombocytopenia with lead-in and continuous dosing

Abstract

3505 Background: ABT-263, a novel, oral BH3 mimetic, potently inhibits multiple antiapoptotic Bcl-2 family proteins. Ongoing phase 1 studies of ABT-263 show anti-tumor activity in CLL and some lymphomas (Wilson W et al, ASH. 2008). However, thrombocytopenia (TCP) due to on-target Bcl-XL inhibition-induced platelet apoptosis is also observed. Platelet nadir occurred on days 3–5 on 14/21 d dosing with each exposure to drug, was proportional to starting platelet count and recovered during therapy due to compensatory increased megakaryopoiesis. TCP was a dose limiting toxicity (DLT) in 3 patients (pts) in CLL study M06–873 (N = 15) where starting platelet counts tend to be low. We tested 2 strategies to mitigate variability in circulating platelet levels and achieve higher cumulative exposure: introducing a lower lead-in dose and using a continuous dosing (CD) (21/21 d schedule). Methods: CD with a 7 d lead-in dose was explored (150, 150 or 100 mg lead-in doses) with dosing at 200 and 275 mg, 225 and 325 mg, or 125 and 250 mg in studies M06–814 (NHL), M06–822 (SCLC), and M06 873 (CLL), respectively. Results: 22 pts on 21/21 d dosing enrolled to date in the 3 studies. Cmax & AUC at steady-state were comparable between pts at the same dose on 21/21 and 14/21 d schedules. Lead-in followed by CD appears to minimize platelet nadir and cycle variability. At 200 mg and grouping data from 200 and 225 mg doses, median platelet nadir in Cycle 1 was 46% and 42% of baseline on the CD schedule after lead-in vs 33% and 36% on the 14/21 schedule, respectively. For pts receiving 150 mg lead-in, nadir occurred during this phase, and platelet levels remained relatively stable on CD for doses up to 225 mg. 2 DLTs were observed for CD, 1 pt per study M06–814 (275 mg) and M06–873 (200 mg) experienced grade 4 (TCP). While CD enrollment and time on study is still limited, anti-tumor activity includes 1 unconfirmed partial response (68% CT regression) in a SLL pt at 275 mg and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months. Conclusions: Dosing schedule moderates early platelet nadir. Optimal dosing regimens may vary between tumor types especially where marrow infiltration is a feature. [Table: see text]