A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma
- Conditions
- Relapsed, Refractory or Plateau Phase Multiple Myeloma
- Interventions
- Registration Number
- NCT00429949
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 21
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dasatinib Dasatinib Dasatinib will be administered continuously at an oral dose of 70 mg BID on Days 1-28 of each 28 day cycle. In patients with stable disease after 8 weeks on therapy the dasatinib will be increased to 100 mg BID on Days 1-28 on each 28 day cycle.
- Primary Outcome Measures
Name Time Method Response Rate [Complete Response (CR) and Partial Response (PR)] Completion of treatment (median duration of therapy was 51 days) CR requires all of the following:
* Absence of the original monoclonal paraprotein in serum and urine by immunofixation, maintained for a minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune response reconstitution does not exclude CR.
* \< 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed. If absence of monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone marrow.
* No increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response).
* Disappearance of soft tissue plasmacytoma
PR requires all of the following:
* 50% reduction in the level of the serum monoclonal paraprotein maintained for a minimum of 6 weeks.
-Reduction in 24 hr urinary light chain excretion by either \> 90% or to \< 200 mg, maintained for a minimum of 6 weeks.
* 50% reduction in the size of soft tissue plas
- Secondary Outcome Measures
Name Time Method Time to Response Completion of treatment (median duration of therapy was 51 days) Time to response is measured from the start of treatment until the first date that criteria are met for complete response or partial response.
Safety and Tolerability of Dasatinib (Grade III-IV Toxicities) Up to 30 days following end of treatment (median duration of therapy was 51 days) Toxicities were graded using the NCI Common Toxicity Criteria v3.0.
Duration of Response Completion of treatment (median duration of therapy was 51 days) Duration of response is measured from the first date that criteria are met for complete response or partial response until the first date that criteria for relapse or progressive disease are met.
Event-free Survival (EFS) for Participants With Plateau Phase Disease Completion of treatment (median duration of therapy was 51 days) EFS is defined as time from the start of the treatment until the first date that criteria for progressive disease are met, therapy was discontinued for toxicity, or death, whichever occurs first. Those patients alive will be censored at the date of last clinical contact. If progression is based upon serum or urine paraprotein measurements, which must be repeated for confirmation, event-free progression is still measured from the start of treatment until the first date that progression is detected.
Event-free Survival (EFS) for Participants With Relapsed Disease Completion of treatment (median duration of therapy was 51 days) EFS is defined as time from the start of the treatment until the first date that criteria for progressive disease are met, therapy was discontinued for toxicity, or death, whichever occurs first. Those patients alive will be censored at the date of last clinical contact. If progression is based upon serum or urine paraprotein measurements, which must be repeated for confirmation, event-free progression is still measured from the start of treatment until the first date that progression is detected.
Trial Locations
- Locations (1)
Washington Universtiy in St. Louis
🇺🇸St. Louis, Missouri, United States