Hu1D10 is a humanized monoclonal antibody directed at a variant of the HLA-DRbeta chain for which clinical responses have been noted in a phase I trial for patients with non-Hodgkin's lymphoma (NHL). We have shown that the 1D10 antigen is present on some chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) tumor cells and that apoptosis can be induced in vitro by exposure to Hu1D10. Based upon these data, we have initiated a therapeutic development plan for Hu1D10 in CLL/SLL. This Quick Trials Proposal forms the first component of this project. The objectives include: (1)To conduct a phase I trial to determine the toxicity profile and maximally tolerated dose of Hu1D10 in patients with CLL/SLL (2) To determine if signalingthrough the syk/lyn pathway following Hu1D10 treatment promotes apoptosis and how this relates to 1D10 antigen expression on tumor cells and changes in disease burden (3)To determine the cell properties that convey resistance to Hu1D10 in CLL/SLL. The proposed schedule is based on PK data from the phase I NHL trial with Hu1Dl0 and rapid clearance of other antibodies (e.g. rituximab) in previously treated CLL/SLL patients. Hu1D10 will be given over a 3-day graduated exposure and once tolerated well, will be given at the dose level specific to the cohort, thrice weekly for 4weeks of therapy. Once the maximally tolerated dose is determined, 12-15 patients will be enrolled to adequately assess safety and to allow analysis of specific correlative studies at the phase I dose to facilitate planning definitive correlative efforts for future phase II studies with this agent. The specific laboratory correlative studies included in this trial are derived from preliminary data with Hu1D10 and other previous monoclonal antibody therapies studied by the investigator in CLL. These studies seek to describe the biologic effects of Hu1D10 in vitro and in vivo with respect to signaling through the syk/lyn pathway and induction of caspase independent apoptosis. Furthermore, studies of cellular features associated with resistance to Hu1D10 therapy are proposed. These laboratory studies combined with clinical data derived from this trial will form the basis for future phase II development of this agent in CLL/SLL.
| Mone, Andrew P; Huang, Peng; Pelicano, Helene et al. (2004) Hu1D10 induces apoptosis concurrent with activation of the AKT survival pathway in human chronic lymphocytic leukemia cells. Blood 103:1846-54 |
