Abstract 2858

Inhibition of B cell receptor signaling is an important mechanism of controlling the proliferation and survival of B cell chronic lymphocytic leukemia (CLL) cells. Lyn, a member of the Src kinase family, couples the B cell receptor to downstream signaling and is over expressed in CLL cells relative to normal B lymphocytes. Lyn is upstream from regulatory kinases in B cells such as PI3 kinase Δ and Bruton's tyrosine kinase, which have been successfully targeted for the treatment of CLL. Addition of Lyn kinase inhibitors to CLL cell cultures accelerates apoptosis; treatment of CLL cells with drugs that induce apoptosis decreases both the activity and amount of Lyn kinase (Contri et al, J Clin Invest, 2005; 115 :369–78). These findings support a critical role for Lyn kinase in CLL pathogenesis by showing correlation between high basal Lyn activity and defects in induction of apoptosis in CLL cells. Thus bafetinib, a limited Src family kinase inhibitor targeting BCR/ABL, Lyn, and Fyn kinases, may suppress the growth of CLL cells by inhibiting Lyn kinase and thus have clinical activity.

Methods and Objectives:

We conducted a single arm, open-label phase 2 trial of single-agent bafetinib in patients with CLL who were relapsed or refractory to > 1course of treatment with either an alkylating agent, rituximab, or a fludaribine-based regimen. Patients were treated with oral bafetinib twice daily (BID), continuously until disease progression or unacceptable toxicity. Endpoints included response assessment by International Working Group CLL Criteria (Hallek et al, Blood, 2008) and toxicity.

Results:

At the time of analysis, 16 patients were administered bafetinib in the intent-to-treat population at 2 study sites (MD Anderson Cancer Center and City of Hope Cancer Center). The median age was 71 years (range 55–88 years); 13 patients were male. 13 patients were Caucasian and 3 were African-American. Of the 12 patients who were tested, 9 had del (17p;13). Patients had received a median of 3 prior treatment regimens (range 1–6). Where indicated, 5/16 (31%) patients were Rai stage I, 5/16 (31%) Rai stage II, 1/16 (6%) Rai stage III and 5/16 (31%) Rai stage IV. 14/16 patients had ECOG performance scores of 0 or 1. The median duration of treatment with bafetinib was 2 months (range 0.25 to 5 months). 11/16 patients were evaluable for response (baseline + > 1 post-baseline evaluation). There were no objective responses by IWCLL 2008 criteria. Partial nodal responses (> 50% reduction in bidimensional measurements in lymph nodes and/or > 50% shrinkage in spleen size) were observed in 7/11 evaluable patients. 2 patients had stable disease post baseline assessments and 2 patients demonstrated progressive disease at their initial evaluation post baseline. 14 patients were evaluable for toxicity. Almost all of the treatment-related adverse events were grade 1 or 2, with fatigue, nausea and elevated liver enzymes being the most common. Grade 1–2 elevated liver enzymes occurred in 9/14 patients; 1/14 patients had a grade 3 elevated liver enzymes and was removed from the study. No patients exhibited elevated bilirubin. One patient with Parkinson's disease had a worsening of his symptoms and was withdrawn from the trial. No treatment-related serious adverse events occurred.

Conclusion:

Bafetinib, a Lyn kinase inhibitor, shows promise in patients with relapsed/refractory B-CLL at a dose of 240 mg orally BID. No treatment-limiting toxicity was observed at this dose level. Preliminary PK analysis from a parallel solid tumor study indicated that peak bafetinib concentrations at this dose only reach 0.3–0.6 μM, which is below the concentrations that inhibit the growth of B-CLL cells in vitro (1–1.5 μM). A higher dose level of 360 mg orally BID is being investigated. Future studies involving combinations of bafetinib with monoclonal antibodies and chemotherapy are planned.

Disclosures:

Kadia:CytRx Corporation: Research Funding. Delioukina:CytRx Corporation: Research Funding. Wieland:CytRx Corporation: Employment, Equity Ownership. Levitt:CytRx Corporation: Employment, Equity Ownership.

Topics:
bilirubin level, increased, chronic b-cell leukemias, chronic lymphocytic leukemia, kinase inhibitors, phase 2 clinical trials, phosphotransferases, toxic effect, transaminitis, adverse event, receptors, antigen, b-cell

Author notes

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Asterisk with author names denotes non-ASH members.

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© 2011 by The American Society of Hematology
2011
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