A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and Efficacy of ABT-263 in Subjects with Refractory or Relapsed Lymphoid Malignancies.

Background: ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity (K_i ≤ 1 nM) to multiple antiapoptotic Bcl-2 family proteins including Bcl-X_L, Bcl-2, Bcl-w, and Bcl-B. ABT-263 displays potent mechanism-based cytotoxicity (EC₅₀ ≤ 1 mM) against human tumor cell lines derived from lymphoid malignancies and small cell lung cancer (SCLC). Pre-clinical experiments on primary patient derived chronic lymphocytic leukemia (CLL) samples with ABT-737, a first generation Bcl-2 family protein inhibitor, induced robust, concentration-dependent apoptosis. The anticipated ABT-263 associated toxicities are mechanism based, in particular, Bcl-X_L mediated decrease in circulating platelet survival, Bcl-w mediated testicular toxicity, and Bcl-2 mediated effects on lymphocytes. ABT-263 is currently being investigated in 3 Phase 1/2a studies in patients with lymphoid malignancies, SCLC/solid tumors, and CLL.

Methods: In this Phase 1/2a study of ABT-263 in subjects with lymphoid malignancies, the Phase 1 dose escalation portion of the study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and recommended Phase 2 dose (RPTD). For each 21-day cycle, subjects receive ABT-263 orally QD for 14 consecutive days followed by 7 days off drug. Pharmacokinetic (PK) assessment was performed at study initiation and on Day 14 of drug dosing. The Phase 2a portion of the study will evaluate ABT-263 at the RPTD in up to 40 subjects with follicular and aggressive NHL to obtain additional safety information and a preliminary assessment of efficacy.

Results: Currently 17 subjects have been enrolled in the lymphoma study. Three subjects completed each of the 10, 20, 40, and 80 mg cohorts enrolled thus far. A Grade 3 DLT (URI resulting in hospitalization treated with antibiotics) occurred in the 160 mg cohort, thus the cohort was expanded to 6. Two patients with bulky SLL/CLL in the 40 and 160 mg cohorts had 95% and 64% tumor reductions after cycles 4 and 2, respectively, and continue on treatment. The PK profile of ABT-263 appeared to be linear between the 10 mg and 160 mg dose levels. The average terminal half-life of ABT-263 varied between 14 and 25 hours across all dose levels. ABT-263 reduced the platelet level in a dose-dependent manner. One subject experienced a Grade 3 thrombocytopenia (platelets 45K/uL) on C1D14, 4 hours post-dosing with 80 mg, resolving 8 hours post-dosing to a platelet count of 162 K/uL. The decreased platelet count did not result in any medical sequelae.

Conclusions: ABT-263 is a novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor that has shown preliminary evidence of activity in lymphoid malignancies.