GX15-070 is a synthetic small molecule which inhibits the binding of the antiapoptotic proteins bcl-2, bcl-xl, bcl-w and mcl-1 to the proapoptotic proteins bax and bak, thus reinstituting programmed cell death in transformed cells. It shows broad single agent cytotoxicity in cancer cell lines in vitro and in vivo. Bcl-2 family proteins are universally overexpressed in CLL in which accumulation of malignant cells is thought to be the direct result of the consequent inability to undergo apoptosis. This Phase I trial was directed at CLL in order to characterize the pharmacodynamic (PD) response to GX15-070. We enrolled 12 patients at doses ranging from 3.5–14 mg/m2 administered using a 1 hr infusion and 3 patients at 20 mg/m2 using a 3 hr infusion. A single intra-patient dose escalation was allowed. Median age was 61 (range 51–76), Rai stage was IV in 10 and median number of prior therapies was 4 (range 2–10). The most frequent adverse events (AE) have been somnolence grade 1 (70%) or 2 (5%) and euphoria grade 1(65%) or 2 (15%) occurring during or shortly following the infusion. There was no correlation with dose and the frequency of these AE's. Other AE's reported in ≥25% of patients were transient O2 desaturation (31%), AST increase (30%) and fatigue (25%). There have been no dose-limiting toxicities to date. Pharmacokinetics (PK) show a tri-exponential concentration-time profile with a rapid initial distribution phase (αt½=0.55 hr), followed by a longer elimination γ phase (t½=39.0 hr). Following a single infusion, AUC increased in a dose proportional manner over the entire range (40.7 to 377.6 ng.hr/mL). PD activity has been noted across all dose levels. 6/7 patients with lymphocytosis at baseline showed reduction of peripheral lymphocyte counts (12–79%). Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA occurred 1–6 hrs after the start of the infusion. A secondary increase peaked with a noticeable lag time from the peak plasma GX15-070 concentration (24 to168 hrs after the start of the infusion). There was a correlation between peak plasma ODNA concentration (median=232.7 range 0–2926 AU/mL) and dose (threshold effect at 14 mg/m2) as well as AUC (threshold effect at 200 ng.hr/mL). Best clinical responses assessed by CLL Workshop Criteria so far are: unconfirmed PR in 1/15; stable disease ≥6 weeks in 7/15. In addition, 4/12 patients with baseline platelet count <150,000/mm3 showed sustained elevations of platelet counts by ≥50% including two patients improving from 70,000 to 144,000/mm3 and 47,000 to 105,000/mm3; 2/4 patients who were anemic at baseline showed sustained elevations of Hb from 8.7 to 11.3 g/dL and 7.9 to 13.9 g/dL, the latter having been transfusion dependent. Conclusions: single agent GX15-070 exhibits dose dependent biological activity in previously treated CLL with documented induction of apoptosis and improvement in hematological parameters at well tolerated doses. Further dose escalations are planned before initiation of a Phase II trial in this patient population.