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

Abstract

Chronic lymphocytic leukemia (CLL) cells express high-levels of Bcl-2-family proteins that inhibit apoptosis, enhancing leukemia-cell survival and drug-resistance. AT-101 (Ascenta Therapeutics, Inc.) is an orally active BH3-mimetic that inhibits the anti-apoptotic activity of Bcl-2, Bcl-XL, and Mcl-1, and induces CLL cells to undergo apoptosis. (Prada et. al., ASH 2005). AT-101 also enhanced the cytotoxicity of rituximab for CLL cells in vitro (James et. al., ASH 2005). These in vitro effects of AT-101 were concentration and time-dependent. We are conducting a phase 2 trial to evaluate the safety and activity of AT-101 by two dosing schedules, used in combination with rituximab to treat patients with relapsed/refractory CLL. We previously reported (Castro et. al., ASH 2006) on 12 patients who received up to 12 weeks of AT-101, 30 mg daily for 3 out of every 4 weeks, with rituximab, 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. Here we describe initial results from a second cohort (n=6) treated with intermittent, “pulse” AT-101, 80 mg/d on days 1–3 and 15–17 of each 28-day cycle, in combination with weekly rituximab, 375 mg/m2/week. To date, 6 patients have received “pulse” AT-101. Patient demographic characteristics and risk prognostic status (ZAP70, IgVH mutational status, and cytogenetics / FISH) are comparable between the two dose cohorts. Gastrointestinal (GI) toxicity, the most notable adverse effect of AT-101 with daily administration, appears reduced with intermittent AT-101; 2/6 patients have had NCI-CTCAE Grade 1–2 GI toxicity, and 0/6 have had Grade 3–4 ileus, compared with 11/12 and 2/12 patients, respectively, in the daily dose cohort. Apoptosis of CLL cells evaluated by Annexin V FACS at the time of maximum AT-101 concentration, was present in 18–45% of cells in 4 of the 6 patients after a single 80 mg dose of AT-101. By comparison, apoptosis after a 30 mg AT-101 dose appeared lower and was detected in approximately 1–15% of cells. After 80 mg of AT-101, plasma concentrations of up to 6.6 μM have been observed compared with concentrations of approximately 0.8–1.8 μM after a 30 mg dose in the daily dose cohort. In the “pulse” AT-101 cohort we have observed partial responses (PR) in 3 patients while the other 3 are still receiving treatment. Five (5) out of 12 patients had a PR in the previously reported AT-101 continuous administration group. Intermittent administration of AT-101 with a “pulse” dose regimen appears associated with an increased pro-apoptotic effect in vivo and higher plasma concentrations, as well as reduced toxicity, when compared with daily dosing. Enrollment continues to confirm these observations and assess whether clinical activity in combination with rituximab is increased with “pulse” dosing of AT-101.

MCL-1 inhibition in cancer treatment

“… 41 , 42 In a Phase II clinical trial in CLL, with a single 80 mg dose of AT-101, apoptosis of CLL cells was detected in 18%–45% of cells by Annexin V flow cytometry analysis in four of the six patients. 43 As a single agent or in combination with the standard of care chemotherapies, AT-101 has been evaluated in more than 20 Phase I and II clinical trials in different types of cancers ( Table 2 ). AT-101 is the first small molecule with potent anti-MCL-1 activity that has been evaluated in clinical trials.…”

Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment

“…AT101 was found to induce apoptosis in CLL cells in vitro and to overcome drug resistance mediated by the microenvironment . It showed a good tolerability and satisfactory efficacy in combination with weekly infusions of rituximab in previously treated patients with CLL .…”

Downregulation of BCL2 by AT‐101 enhances the antileukaemic effect of lenalidomide both by an immune dependant and independent manner

“…This Phase III clinical trial confirmed, for the first time, a positive impact of targeting BCL2 in patients with CLL (O’Brien et al , 2009). AT‐101 also demonstrated an ORR of 38% among patients with relapsed or refractory CLL (Castro et al , 2007, 2006) when used in combination with the immunotherapeutic rituximab. These results suggest that BCL2 downregulation can potentially enhance the anti‐leukaemic effects of chemotherapy and/or immunotherapies.…”