A Phase II, Open Label Study of AT-101 in Combination with Rituximab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) cells express high-levels of Bcl-2 and related anti-apoptotic proteins that collectively can enhance leukemia-cell survival and drug-resistance. AT-101 is an orally active BH3-mimetic that can inhibit the anti-apoptotic activity of Bcl-2-family-member proteins (e.g. Bcl-2, Bcl-XL, Mcl-1) and induce CLL cells to undergo apoptosis. Furthermore, we found that AT-101 also can enhance the cytotoxicity of rituximab for CLL cells in vitro. As such we conducted a phase 2 trial to evaluate the safety and activity of AT-101 when used together with rituximab to treat 12 patients who had relapsed/refractory CLL. Patients received AT-101, at 30 mg/d, for 21 or 28 days during each of three 28-day cycles. Rituximab was administered at 375 mg/m2 for 12 doses (total dose = 4,500 mg/m2) on days 1, 3, 5, 8, 15, 22, 29, 31, 33, 40, 57, 59, 61. The first dose of rituximab was given over two days to minimize infusion-related adverse events. The patients’ median age was 61.5 years (range 43–81). Nine patients were high risk and 3 were intermediate risk based on the modified Rai classification and had received a median of 2 prior regimens (range 1–8). Six patients had leukemia cells that expressed ZAP-70 and/or unmutated immunoglobulin variable region genes and 4 patients had either 11q deletions or complex cytogenetics. Six patients interrupted treatment due to adverse events, most of which were transient and without residual complications. Grade 1–2 gastrointestinal effects (e.g., nausea, vomiting) occurred in 11 patients, 2 of whom had grade 3/4 ileus. Six patients experienced treatment-associated fatigue (grade 1–2 in 5 and grade 3 in one). Other than ileus and fatigue the only grade 3/4 event noted was neutropenia. One patient without neutropenia died while undergoing treatment from community-acquired bacterial pneumonia[j1]. Pharmacokinetic studies demonstrated that the average Cmax of AT-101 was 565 ng/ml (280 – 805 ng/ml) at a Tmax of 3.1 hours (1.7 – 5.6 hrs.). Correlative science studies performed on leukemia cells isolated at various times after treatment demonstrated leukemia-cell apoptosis in vivo, with maximum levels seen at times when we observed peak drug levels of AT-101. Eight patients had completed the study and had full response evaluation at the time of this abstract’s submission. The overall response rate was 38% [CRu (2); PR (1); SD (3); PD (2)]. Four of eight patients (50%) had significant reductions in leukemia cell counts and splenomegaly and 5 of 8 (63%) had reductions in lymphadenopathy. AT-101 in combination with Rituximab has apparent activity in patients with relapsed-refractory high-risk CLL. Additional enrollment is planned using alternate AT-101 schedules in an attempt to increase peak plasma concentrations (and potentially activity) and reduce GI toxicity.