Relapsed, Refractory or Plateau Phase Multiple Myeloma Clinical Trial
Official title:
A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma
To evaluate the response rate (Complete Response [CR] and Partial Response [PR]) to dasatinib in patients with relapsed, refractory or plateau phase multiple myeloma whose serum paraprotein levels are >0.5g/dL or urine paraprotein levels are >1.0g/24 hours.
Studies have confirmed the ability of dasatinib to inhibit numerous kinases (76 of 148
kinases tested in one series).13 Overexpression or dysregulation of a number of kinases have
been implicated in the pathophysiology of MM and could serve as potential targets for
inhibition by dasatinib.
Fibroblast growth factor 3 (FGFR3), which is not normally expressed in plasma cells, is
aberrantly expressed in 15 % of multiple myeloma patients. Its expression results from the
translocation t4;14.14 Dasatinib weakly inhibits FGFR3.13
Another target for inhibition in multiple myeloma is the epidermal growth factor receptor
family, particularly ErbB4. In vitro, ErbB4 was expressed in 4 of 9 myeloma cell lines, and
a panErbB inhibitor induces apoptosis in myeloma cell lines.15 Dasatinib has been shown to
have moderate affinity for ErbB4.13
Members of the src family of protein-tyrosine kinases are also potential targets for therapy
in multiple myeloma. Hematopoietic cell kinase (Hck) is a src family member whose expression
is restricted to hematopoietic cells of the myeloid and B-lymphoid lineages. Hck mediates
IL-6 induced proliferative signals, which are potent growth and survival factors in multiple
myeloma.16 Lyn and Fyn are two additional src family protein-tyrosine kinases that may serve
as targets for therapy in myeloma. Lyn is strongly expressed in myeloma cell lines, while
Fyn expression is variable. Activation of Lyn and Fyn appears requisite to IL-6-induced
proliferation.17 Selective inhibition of Lyn in vitro suppresses IL-6 induced
proliferation.18 Dasatinib has high affinity for both Fyn and Lyn, and inhibition may reduce
IL-6 induced proliferation.13
The receptor tyrosine kinase c-kit is overexpressed in one-third of cases of multiple
myeloma. 19 Inhibition of c-kit with imatinib results in inhibition of proliferation in
vitro.20 Unfortunately, in a phase II clinical study of imatinib in relapsed/refractory
myeloma, there were no responses.21 However, dasatinib binds c-kit with greater avidity than
does imatinib.13
Myeloma cells are heterogeneous in their biological characteristics, such as their
proliferative response to IL-6, as well as their immunophenotypes, including CD45
expression. The promiscuous nature of kinase inhibition by dasatinib may tolerate small
changes in the kinase and remain able to inhibit mutant kinases.
In addition to potential antimyeloma effects of dasatinib, there are potentially additional
benefits. Src plays an essential role in osteoclast function and bone resorption.22 As a Src
inhibitor, dasatinib inhibits bone resorption in vitro. 11 Src inhibition by dasatinib in
patients with multiple myeloma could produce beneficial effects on bone density.
We propose a single-arm, phase II, open-label study of dasatinib in patients with relapsed
or plateau-phase multiple myeloma.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment