Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).

The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.

Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl-mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.

Murine monoclonal antibody (MAb) L6 binds to an antigen expressed on the surface of breast, colon, ovary, and nonsmall-cell lung cancer. This antibody effects antibody-dependent cellular cytotoxicity (ADCC) with human mononuclear cells and complement-dependent cytotoxicity (CDC) with human complement. Because of these activities, we conducted a phase I trial of MAb L6 in patients with advanced cancer. Nineteen patients whose tumors highly expressed antigen were selected for this trial. Eighteen were evaluable. MAb L6 was administered at dose levels ranging from 5 mg/m2/d to 400 mg/m2/d for 7 days and was well tolerated. The only side effects detected were fever and headaches at the highest dose levels. The serum half-life of L6 was directly related to dose and ranged from a mean of 7.7 hours at 5 mg/m2/d to 29.1 hours at 400 mg/m2/d. Peak serum concentrations ranged from 0.22 micrograms/mL to 362 micrograms/mL. Biopsies at the end of treatment showed L6 to localize well to tumor cells with apparent in vivo saturation occurring at dose levels above 100 mg/m2/d. Thirteen patients formed human antimouse antibodies (HAMA), some as early as day 13. One patient with recurrent breast cancer on the chest wall achieved a complete remission. The response was first noted at 5 weeks and a pathologic complete remission occurred at 14 weeks. Because of its favorable binding properties and the encouraging clinical effect observed, future evaluation of this MAb appears warranted.

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