Phase 3 Randomized Trial of Fludarabine/Cyclophosphamide Chemotherapy with or without Oblimersen Sodium (Bcl-2 Antisense; Genasense; G3139) for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).

Bcl-2 is an anti-apoptotic protein that has been closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Preliminary studies showed that oblimersen, an antisense oligonucleotide that targets Bcl-2, enhanced apoptosis induced by fludarabine (Flu), dexamethasone, and rituximab in cultured CLL cells. In a Phase 1 study, oblimersen displayed modest single-agent activity in CLL pts who had received extensive prior therapy. We conducted a randomized, multinational, Phase 3 trial of chemotherapy given with or without oblimersen in pts with advanced CLL. Eligibility included: symptomatic disease; intermediate or high-risk Rai stage; ≥ 1 Flu-containing regimen; ECOG PS ≤ 2; adequate organ function. Exclusions: stem cell/allogeneic transplant; autoimmune anemia/thrombocytopenia. Pre-randomization strata: prior treatment (1 or 2 vs. ≥ 3 regimens); response vs. refractory to prior Flu; and response duration to last therapy (> or ≤ 6 mos). All pts received Flu 25 mg/m²/d, plus cyclophosphamide (Cy) 250 mg/m²/d, daily for 3 days. Pts randomized to oblimersen received 3 mg/kg/d x 7 days by IV infusion, beginning 4 days before Flu/Cy and on each day of Flu/Cy treatment. Subsequent cycles were repeated every 28 days, for a maximum of 6 cycles, or to the time of CR, intolerable toxicity, or progression. All pts received prophylactic filgrastim, TMP/SMZ, and acyclovir. Response assessment was conducted at every cycle during treatment, and every 2 months thereafter for up to 36 months. The primary endpoint of the study was to compare the proportion of pts who achieved complete (CR) and nodular partial (nPR) responses. Secondary endpoints included: overall response rates (CR/nPR/PR); durable responses; response duration; time-to-progression; clinical benefit; and safety. Bone marrows in responding pts underwent central blinded review. A total of 241 pts were randomized; the last patient was enrolled in the 2^nd quarter 2003. All pts have completed ≥ 1 year of follow-up, and results of this trial will be presented.