A Phase II Study of AT7519M, a CDK Inhibitor, in Patients with Chronic Lymphocytic Leukemia: NCIC CTG Trial IND.193

Introduction: The prognosis of patients (pts) with relapsed or refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) is poor. AT7519M is a small molecule inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 4, 5 and 9 with lower potency against CDKs 3, 6 and 7. AT7519 has potent anti-proliferative activity against peripheral blood mononuclear cells isolated from CLL patients. Exposure of CLL cells to AT7519 results in cell cycle arrest and, ultimately, cell death by apoptosis. Based on the results of a NCIC CTG phase I study in advanced malignancies, the recommended phase II dose (RP2D) was 27 mg/m² given as a 1 hour infusion twice weekly for 2 out of every 3 weeks. Using this schedule, Tumor Lysis Syndrome (TLS) and QTc prolongation were not observed.

Methods: In a phase II clinical trial, we evaluated the clinical and pharmacodynamic effects of AT7519 using the RP2D schedule in pts with rel/ref CLL. Eligible patients were those with documented CLL with at least one prior systemic treatment regimen and either lymphocyte count > 10 x 10⁹/L or at least one measurable lymph node > 2 cm x 2 cm. The primary objective was complete or partial remission (CR/PR) as defined by the 2008 International Working Group (IWG) Guidelines. We used a Fleming Phase II design, aiming for a total of 30 subjects, assuming an H_A of >0.20. Cycle 1, dose 1 was administered as an in-patient with prophylaxis and monitoring for TLS.

Results: Seven pts were accrued over 16 months. As a result, the trial was prematurely closed. Reasons for slow accrual included concerns about the risk of TLS, the need for in-patient care during cycle 1, and the relative stringency of eligibility criteria regarding baseline hematopoietic and renal function. All seven pts were male, with median age 70 years (range 47-81). Median number of previous regimens was 3 (range 1-4). Two pts had 11q- and one had 17p-. A total of 21 cycles were administered (median 4 cycles) with 71% of patients receiving > 90% of the planned dose intensity. Two pts required a dose reduction due to thrombocytopenia and one of these patients came off study early due to hypoxia and fever. The most common non-hematologic adverse events that were at least possibly related were grade 1 and 3 fatigue, grade 1 nausea (57%), grade 1 diarrhea and grade1/2 anorexia (43%) and grade1/2 fever (29%). Hematologic toxicities were primarily grade 1 and 2. One pt developed grade 4 neutropenia and grade 3 thrombocytopenia on cycle 1 day 2; a second patient developed grade 3 thrombocytopenia on C1D2. Both required dose reductions and counts recovered. Biochemical toxicity was minimal; all grade 1 except one pt with transient grade 2 bilirubin and 2 pts with grade 2 hypophosphatemia. According to the protocol defined 2008 IWG response assessment criteria, there were no responses observed. Four pts had stable disease (SD), two pts had progressive disease (PD) and one pt was inevaluable (came off due to toxicity after 2 doses). However, updated response criteria for CLL recommend that lymphocytosis alone should not be considered evidence of progressive disease in clinical trials testing novel agents that affect cellular migration and adhesion. Based on these new criteria, 1 of 7 patients developed PD, 3 demonstrated tumor shrinkage at time of coming off protocol therapy including 2 with corresponding improvement in blood counts although none achieved objective partial response (see Table).

Conclusion: The CDK inhibitor, AT7519M was safely administered to pts with rel/ref CLL. While some patients had tumor shrinkage, there were no objective responses over the course of this study. Unfortunately, the small sample size of this trial precluded any other definitive conclusions.

Table:

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Responses Graded By Traditional and Revised CLL Response Criteria

Table:

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Responses Graded By Traditional and Revised CLL Response Criteria

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